Response of Steroid-Refractory Acute GVHD to α 1 -Antitrypsin

Abstract

α1-Antitrypsin (AAT) is a serine protease inhibitor with anti-inflammatory, antiapoptotic, and immunomodulatory properties. It has therapeutic efficacy in animal models of autoimmune diseases, inflammatory disorders, and transplantation. In a phase I/II open-label single-center study, we administered AAT (Glassia; Baxalta/Kamada, New Ziona, Israel) as salvage therapy to 12 patients with steroid-refractory acute graft-versus-host disease (GVHD). AAT was given i.v. at 2 dose levels over a 15-day course. All patients had grades III or IV GVHD with stage 4 gut involvement. After treatment, plasma AAT levels increased in both cohorts and remained within 2 to 4 mg/mL for the duration of treatment. No clinically relevant toxicities attributable to AAT were observed. GVHD manifestations improved in 8 of 12 patients, and 4 responses were complete. Six patients (50%) were alive at last follow-up (>104 to >820 days). These findings show that AAT is well tolerated and has efficacy in the treatment of steroid-refractory severe acute GVHD. Further studies are warranted.

Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives

“…AAT homeostasis after allo-HCT may be important for regulating allogeneic responses because elevated AAT clearance in stool was correlated with the severity of GI-GVHD and steroid resistant GVHD (SR-GVHD) in some studies (171–173), but not others (174). Consistent with this, we and others have demonstrated that AAT treatment for SR-GVHD-improved GVHD manifestations without significant adverse effects or increased rates of infection in a multicenter prospective or single institution phase I/II study (175, 176). This data indicates that AAT may be a rational first-line therapy for SR-GVHD or other high risk GVHD, which is associated with high mortality.…”

Alpha‐1‐antitrypsin for the treatment of steroid‐refractory acute gastrointestinal graft‐versus‐host disease

“…In the study by Mercondes et al 33% of patients had a CR to AAT, and all patients received the drug as second line. 4 In contrast, three out of the 7 patients in our study received AAT beyond second line and none of our patients achieved a CR with this agent alone. Additionally, all patients in our series had overall grade III-IV disease at presentation compared to 16% (n 5 2) in the previous study, which could be a possible reason for discrepant suboptimal activity seen in our series.…”

Acute Graft‐versus‐Host Disease: Emerging Insights and Updates into Detection, Prevention, and Treatment

“…Suppression of GVHD with AAT is thought to occur via inflammatory cytokine reduction and increased production of regulatory T cells. 75 Recent small phase I and II studies demonstrated that complete responses were achievable when AAT was administered as salvage therapy. 75,76 A prospective dose-finding study used AAT in a cohort of patients (N=12) presenting with grades III or IV GI only, or GI with liver, acute GVHD who failed steroid treatment.…”

“…75 Recent small phase I and II studies demonstrated that complete responses were achievable when AAT was administered as salvage therapy. 75,76 A prospective dose-finding study used AAT in a cohort of patients (N=12) presenting with grades III or IV GI only, or GI with liver, acute GVHD who failed steroid treatment. An initial loading dose of AAT 90 mg/kg intravenous on day 1 was given followed by seven maintenance doses on days 3, 5, 7, 9, 11, 13, 15 of either 30-60 mg/kg/day depending on the dosing cohort.…”