Abstract Background Steroid-refractory acute graft versus host disease (SR-aGVHD) can be a life-threatening complication of allogenic hematopoietic cell transplant (HCT). Ruxolitinib is the only FDA-approved treatment for SR-aGVHD, and currently there is no agreed upon next line therapy. Alpha-1 antitrypsin (AAT) has shown promise as a potential treatment option in aGVHD and SR-aGVHD. We analyzed the efficacy of AAT in treatment-refractory aGVHD patients, wherein patients had been previously treated with multiple lines of therapy. Methods We identified 33 patients with SR-aGVHD who received AAT 120 mg/kg IV twice weekly for four weeks, followed by once weekly maintenance infusions for four weeks. Patients with Grade I-IV aGVHD based on the Mt Sinai Acute GVHD International Criteria (MAGIC) on D0 of AAT were included, and all patients met criteria for SR disease. Most patients (n=22) had been treated with ruxolitinib prior to starting treatment with AAT. GVHD grade was compared from D0 of AAT to D28 and D56 and classified as complete (CR), partial (PR), mixed (MR), nonresponse (NR) or progression of disease (PD). The primary objective was overall response rate (ORR), defined as CR or PR, to AAT in SR-aGVHD disease at D28. Secondary objectives included ORR at D56, CR and PR at D28 and D56, durable response rate at D56, response rates in those with severe disease (Grade III-IV), safety, tolerability, percent decrease in corticosteroid dose and infectious complications within 100 days after starting AAT. Response outcomes were analyzed using proportions with 95% confidence intervals. Proportions were calculated using the number of patients who had started AAT, deaths were considered NR. Results The D28 primary endpoint was reached in 22/33 patients with ORR 66.7% (95% CI: 48.2%-82.0%) - similar to the ORR of 62.3% seen in the REACH2 trial with ruxolitinib. Durable response was seen in 17/33 patients (51.5%, 95% CI: 33.5%-69.2%) compared to the 39.6% durable response rate in REACH2. ORR at D56 was reached in 19/33 patients with ORR= 57.6% (95% CI: 39.2%-74.5%). Three deaths occurred before D28, and an additional 4 deaths occurred before D56, predominantly due to aGVHD and infectious complications. 13 patients went on to next line therapies after AAT, 6 of those were within the 56 days of AAT treatment. Most patients (n=22, 66.7%) had been treated with ruxolitinib prior to starting AAT and were therefore considered treatment refractory. In this cohort, the median days between starting ruxolitinib and AAT was 18 days. In this subgroup, 14/22 (ORR=63.6%) responded at D28 of AAT, and 12/22 (ORR=54.54%) responded at D56. Of those, 14/22 (63.6%) remained on ruxolitinib at D56. These response rates are similar to those of the broader cohort. The severe disease subgroup (n=17) with Grade III-IV aGVHD showed similar response rates to the overall cohort. At D28, 12/17 responded (ORR 70.5%, 95% CI: 44.0%-89.7%) and 11/17 responded at D56 (ORR 64.7%, 95% CI: 38.3%-85.7%). At D0 of AAT, 19 patients (58%) were on ≥1 mg/kg/d of prednisone equivalents; 27 patients (82%) were on ≥0.5 mg/kg/d. At D56, 17 patients (51.5%) were on less than 0.5mg/kg/d of prednisone. On average, patients decreased their prednisone dose by 0.69 mg/kg/d by D56. Few side effects were reported, and no patients halted therapy due to side effects. At D100 of AAT, 21/33 patients (63.6%) had been diagnosed with a bacterial infection and 24/33 (72.7%) had been diagnosed with a viral infection, and no fungal infections were diagnosed. Conclusion This is the first report of the efficacy of alpha-1 antitrypsin after ruxolitinib failure or intolerance, demonstrating the real-world clinical benefit to patients with aGVHD refractory to multiple lines of therapy. AAT induces responses on par with ruxolitinib despite previous ruxolitinib exposure with improved durability of response. AAT was also effective at reducing corticosteroid use in this immunocompromised population. High rates of infection were observed likely due to the heavy pre-treatment in this sick population. Rates of infection were also captured for an extended period. The addition or switch to AAT notably demonstrated high ORR in Gr III-IV treatment-refractory disease with no adverse effects attributed to AAT.
Castellani et al. (Mon,) studied this question.