Sirolimus Plus Roxadustat in Patients with Pure Red Cell Aplasia: Results from a Prospective Multi-Center Clinical Trial

BACKGROUND Pure red cell aplasia (PRCA) is a rare disease and the treatment is still challenging. We investigated the safety and efficacy of sirolimus plus roxadustat in patients with acquired PRCA. METHODS Sirolimus was initiated at a dose of 0.03 mg/kg/day and adjusted according to concentration monitoring. Roxadustat was administered at a dose of 70 mg three times a week. Treatment efficacy was evaluated 3 and 6 months after treatment. Changes in hemoglobin concentration and quality of life and achievement of transfusion independence were also evaluated. RESULTS Between October 2022 and January 2024, a total of 82 patients with acquired PRCA were enrolled in the clinical trial. The median age was 63 years, with 44 newly diagnosed cases and 38 relapsed/refractory cases. Ten patients withdrew during the trial period and 72 patients completed the trial. Median duration of sirolimus plus roxadustat treatment was 465 days (range, 123-625). The median time of response was 35.5 days (range, 10-180). Median time to achieve complete response (CR) was 76 days (range, 30-390). Sirolimus plus roxadustat produced an overall response (OR) in 65/72 patients (90.3%), including 39/72 (54.2%) CR and 26/72 (36.1%) partial response (PR), at 3 months after initiation. Compared to newly diagnosed PRCA, relapsed/refractory PRCA (R/R PRCA) achieved comparable OR rate at 3 months (92.7% vs. 87.1%, P=0.428). Median time to achieve CR in newly diagnosed PRCA was 33.5 days, which was slightly less than 41 days in R/R PRCA, and it did not reach statistical significance (P=0.377). However, the 3-month CR rate was higher in newly diagnosed patients than those with R/R PRCA (65.9% vs. 38.7%, P= 0.022). The 6-month rate of OR in total cohort was 93.0%, with CR and PR being 77.5% and 15.5%, respectively. No significant difference in OR rate between newly diagnosed PRCA and R/R PRCA at 6 months point (95.1% vs. 90.0%, P = 0.405).The 6-month CR rate was slightly higher in newly diagnosed patients than those with R/R PRCA (85.4% vs. 66.7%), but the difference was not significant (P = 0.062). Mean hemoglobin concentration increased from 55.1 ± 15.6 g/L at baseline to 115.6 ± 24.8 g/L after 6 months of treatment. The proportion of patients who achieved transfusion independence within 1, 2, and 3 months of treatment was 57.4%, 76.6%, and 89.5%, respectively. Reticulocyte count increased temporarily in the first month after treatment and then gradually decreased to normal fluctuating levels.Compared with baseline, serum ferritin decreased from 1645±2360 ng/ml to 582±449 ng/ml, and erythropoietin concentrations decreased from 1040±712 ng/ml to 161±188 ng/ml after 6 month of treatment. Functional Assessment of Chronic Illness Therapy-Fatigue score and SF-36 score significantly improved after treatment. We also compared the response of sirolimus plus roxadustat from this study with the response observed in other therapies. Sirolimus plus roxadustat showed quicker response and superior OR rate than that of CsA therapy in newly diagnosed PRCA. For R/R PRCA, addition of roxadustat to sirolimus significantly improved OR at 3 months and shortened the response time. Adverse events occurred in 24 patients (29.2%), including 4 cases (4.9%) with severe adverse events. The adverse events included: oral mucositis, pneumonia, increased creatinine concentration, mild liver dysfunction, thrombocytopenia, leukopenia, hyperglycaemia, hyperlipidemia and edema. Until last follow-up date, two patients experienced relapse after treatment and 4 patients died from pneumonia. CONCLUSIONS Sirolimus plus roxadustat is an effective treatment for PRCA and has an acceptable safety profile. (Chinese Clinical Trial Register number, ChiCTR2200065107).