Alpha‐1‐antitrypsin for the treatment of steroid‐refractory acute gastrointestinal graft‐versus‐host disease
Authors: James H. Jerkins, Mehdi Hamadani, Felicia Zook, Narendranath Epperla, Bronwen E. Shaw, Wael Saber, J. Douglas Rizzo, Marcelo Pasquini, Saurabh Chhabra, William R. Drobyski, Parameswaran N. Hari, Nirav N. Shah
Journal: American Journal of Hematology (2017)

Acute graft-versus-host-disease (GVHD) is a common cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT).1 Among GVHD target organs, severe involvement of the lower gastrointestinal (GI) tract has limited therapeutic options. Systemic corticosteroids are generally the frontline treatment for most patients.2 Despite treatment, development of steroid-refractory acute GI GVHD remains a common complication with a dismal long-term prognosis.2 Alpha-1-antitrypsin (AAT) is a 52 kDa glycoprotein that is produced mainly by the liver.3 It has been found to reduce circulating pro-inflammatory cytokines resulting in improvement in the severity of GVHD in murine models.3 A phase I/II study (n = 12) reported activity of AAT in patients with steroid-refractory GI GVHD.4 Eight of the 12 patients treated had a clinical response with four complete responses (CR) in the GI tract. We report here a retrospective series of patients with steroid-refractory acute GI GVHD who received AAT at our center from 01/2015–04/2017. The study was approved by the Institutional Review Board. Steroid-refractory acute GVHD was defined as (1) progressive GVHD after ≥3 days of systemic corticosteroids (≥ 1 mg/kg/day of prednisone equivalent) or (2) no improvement in GVHD after at least 7 days on ≥1 mg/kg/day of prednisone equivalent.5 Acute GVHD grading was according to the Consensus criteria.6 Response to AAT was defined by the following standard criteria5: CR was resolution of all signs and symptoms of GVHD in all organs. A partial response (PR) was an improvement in one or more organs involved with GVHD symptoms without progression in others and with no intervening salvage therapy. No response (NR) was defined as absence of any improvement or progression. To assess the durability of responses to AAT, we evaluated GVHD-flare free and additional immunosuppression-free (GVHD-F/A-IST-free) survival 3-months after starting AAT. For this endpoint patients experiencing a GVHD flare after AAT therapy, those not responding to AAT, those requiring additional immunosuppressive agents to control GVHD, or those who died were considered therapy failures. Seven patients with steroid-refractory lower GI GVHD at our center received off-label AAT (Glassia; Baxalta/Shire, Dublin, Ireland). Patient demographics are summarized in Table 1. All patients were treated with 1.6 mg/kg methylprednisolone (or equivalent) as frontline therapy. Patients with steroid-refractory GVHD received an initial loading dose of AAT intravenously (IV) at 90 mg/kg followed by 30 mg/kg IV every other day for 6 doses. This was followed by a maintenance dose of 120 mg/kg IV weekly for seven weeks in responding patients. Four patients received AAT as the first therapy option after demonstrating steroid-refractory GVHD, while three patients received it as a subsequent line of treatment. The median interval between initial acute GVHD diagnosis and administration of AAT was 36 days (range 5–124 days). No adverse events related to AAT were seen. Among the seven treated patients, three had a PR at day 28; however, there were no CRs (Table 1). Six patients were evaluable for 3-month GVHD-F/A-IST-free endpoint, and none had a sustained response to AAT. One (non-evaluable) patient with PR is currently 6 weeks post therapy initiation. Four patients died due to GVHD-related complications with a median time to death post GVHD diagnosis of 138 days (Range 83–217). GVHD 28-day response to AAT Over the last 2 years, several novel agents have demonstrated promise for steroid-refractory GI GVHD, however no agent has been shown to be efficacious in a randomized controlled trial. Patients with steroid-refractory GVHD often do not respond to second-line therapies, and even when they do respond, they frequently experience a flare in their disease requiring subsequent therapy as was seen in our experience with AAT. To assess durability of responses, we utilized an alternative endpoint, GVHD-F/A-IST-free, at 3 months to assess the number of patients who were still responding and free from additional therapies targeting GVHD. 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 = 2) in the previous study, which could be a possible reason for discrepant suboptimal activity seen in our series. It is possible the up-front application of AAT in GVHD management before steroid-refractory disease is established might be more beneficial. A multi-center trial evaluating AAT's use prior to development of steroid-refractory disease is currently underway (NCT02956122), and hopefully will clarify role of this agent as frontline therapy of acute GI GVHD. James H. Jerkins assisted in collecting of the data, analysis as well as writing the paper. Mehdi Hamadani, and Nirav Shah assisted in analysis of the data, writing the paper and critically revising the paper. Felicia Zook assisted in collection of the data and critically revising the paper. Mehdi Hamadani, Marcelo Pasquini, Parameswaran N. Hari, and Nirav Shah provided patients for the paper Narendranath Epperla, Bronwen Shaw, Wael Saber, J. Douglas Rizzo, Marcelo Pasquini, Felicia Zook, Saurabh Chhabra, William R. Drobyski, Parameswaran N. Hari critically revised the paper.