Treatment with sirolimus for refractory/relapsed primary or secondary warm autoimmune hemolytic anemia/evans syndrome: A single centre prospective study

Abstract Background There are unmet needs for patients with warm antibody autoimmune haemolytic anaemia (wAIHA) and Evans syndrome (ES) who are refractory/relapsed to steroids or other second or third line therapies. Mammalian target of rapamycin(mTOR) inhibitor sirolimus has been demonstrated effective in some retrospective studies. This study aimed to assess the efficacy and safety of sirolimus for refractory/relapsed wAIHA and ES prospectively. Methods This single centre prospective study was conducted at Peking Union Medical College Hospital (PUMCH). Patients diagnosed with primary or secondary wAIHA and ES who were refractory/relapsed to at least full dose and duration of glucocorticoid were enrolled. After signing the consent forms, participants received sirolimus at a dosage of 1-3 mg/day and maintained the tough concentration of 4-12ng/ml. Patients had to be treated for at least 6 months and continued the treatment till the end of follow-up if responded. Regular follow-up assessments were performed for a minimum duration of 12 months. The primary endpoints of the study were the overall response rate (ORR) and the complete response rate (CRR) at 6-month. Secondary endpoints included ORR and CRR at 12-month, safety and recurrence rates. This study was registered at clinical trials.gov (NCT05925023). Results Between June 2023 and October 2024, 78 patients (28 males, 50 females) were finally enrolled. 63 (80.8%) patients were diagnosed as wAIHA and 15 (19.2%) patients as ES. The median age was 52 (interquartile range [IQR] 38–65) year-old, with 10.3%(8/78) transfusion dependent (TD). The overall response rate was 76.9%(60/78), 80.7%(63/78), 78.9%(56/71) at 3, 6 and 12-month, the complete response rate was 39.7%(31/78), 51.3%(40/78), 52.1%(37/71) respectively. The time to achieve OR and CR were 26 days (IQR 25–93), 76 days (IQR 30–180), respectively. In a median of 13.9 months(IQR 12.7–17.0) follow-up time, 28.2%(22/78) patients reported treatment-emergent adverse events(TEAEs). The most common TEAEs were mucositis (15.4%), infections (7.7%) and gastrointestinal disorder(6.4%). All were mild and reversable under systemic treatments. Relapse happened in 12.7%(9/71) of patients. 2.8% (2/71) died at the end of follow-up. In both univariate and multivariate regression analysis, no factors were found to predict significantly OR, CR at 6-month(p>0.05). Conclusion Sirolimus was effective for patients with primary refractory/relapsed wAIHA and ES, with mild side effects and low relapse rate.