Use of Calcineurin Inhibitor (CNI) and Eltrombopag (EPAG) Among Patients with Acquired Aplastic Anemia (AA) in the United States: Results from a Large National Database
Authors: Stempel Jessica M. , Wang Rong , Lee Alfred I , Ma Xiaomei , Podoltsev Nikolai A. 
Published: December 2024

XM, NAP are co-senior authors
Background
AA is a rare autoimmune disorder leading to bone marrow failure, pancytopenia, infections, and bleeding complications. The recommended management of transplant-ineligible patients (pts) with newly diagnosed severe AA (SAA) is the combination of horse anti-thymocyte globulin (hATG), CNI and EPAG (triple therapy; Peffault de Latour, NEJM 2022). The SOAR trial (Scheinberg, Lancet Haematol 2024) reported that CNI + EPAG can reduce the transfusion burden with the understanding that this combination should not replace triple therapy for SAA if hATG is available and not contraindicated. Real-world data on CNI + EPAG use for AA is limited.
Methods
We conducted a retrospective cohort study leveraging the Blue Cross Blue Shield (BCBS) Axis database, which captures healthcare claims of about 1/3 of the population in the United States (US). We included pts with AA ≥18 years (yrs) of age, diagnosed from 07/01/2016 through 06/30/2022, covered by BCBS continuously from 6 months (mo) before the diagnosis to at least 6 mo after initiation of AA-directed treatment. We selected pts who started treatment within 6 mo of diagnosis and defined concurrent CNI + EPAG users as those having both prescriptions within 3 mo and with ≥1 mo of overlap during the 6-mo period. We recorded the number of transfusions of red blood cells (RBC) and platelets (PLT) at baseline (8 weeks [wks] before initiation of AA-directed treatment) and in the last 8 wks of the 6 mo of treatment (response assessment period). We categorized transfusion status at baseline as: transfusion independent (TI) (0 transfusion of RBCs and/or PLTs), low transfusion burden (LTB) (1-3 transfusions) and high TB (HTB) (≥4 transfusions). The outcomes of interest were transfusion independence for all subgroups and reduction by ≥50% for pts with HTB during the response assessment period. We used paired Student t-test to assess TB differences between the two periods.
Results
We identified 153 pts with AA treated with CNI + EPAG. Median age at diagnosis was 51 (interquartile range [IQR]: 34-59) yrs, 53 (34.6%) were &lt;40 yrs. Most pts were female (81, 52.9%) and were in the Southern (48, 33.4%) or Mid-western (42, 29.4%) US regions. Based on social deprivation index, more pts were in the 1st tertile, corresponding to the highest socioeconomic status (68, 44.4%). 67 pts (43.8%) had an Elixhauser comorbidity score of ≥3, indicating higher comorbidity severity.
The median time from AA diagnosis to initiation of CNI + EPAG was 17 (IQR: 8-29) days. 136 pts (88.9%) only received cyclosporine, 9 (5.9%) received tacrolimus, and 8 (5.2%) pts switched CNI agent during the treatment period. 123 pts (80.4%) had CNI levels measured at least once during the 1st mo of treatment (median, 4 [IQR: 1-6] times). Within the 6 mo of treatment, 137 pts (89.5%) had CNI levels measured (median, 17 [IQR: 7-24] times). The median starting dose for EPAG was 150 mg (108 pts, 70.6%) with 2 pts (1.3%) starting at higher doses and 43 (28.1%) at lower doses. Pts remained on both CNI + EPAG for a median of 171 (IQR: 141-182) days and had a median proportion of days covered with both during 6 mo of treatment of 99.4% (IQR: 93.9-100), indicating adherence to double therapy.
At baseline, 56 pts (36.6%) were TI; 48 (31.4%) pts had LTB, and 49 (32.0%) pts had HTB. The median number of baseline RBC and PLT transfusions was 3 (IQR: 2-5) and 5 (IQR:4-6), respectively. Twelve (21.4%) out of 56 pts who were TI at baseline received transfusions during the response assessment period. Among the 97 pts who received any type of transfusion at baseline, 64 (66%) became TI, including 34 (70.8%) and 30 (61.2%) who had LTB and HTB at baseline, respectively. Among 49 pts with baseline HTB, a ≥50% TB reduction was observed in 37 pts (75.5%). Among all 153 patients, the mean difference in the number of transfusions between baseline and the response assessment period was 1.20 (95% confidence interval: 0.59-1.81, p&lt;0.001).
Conclusions
Our real-world analysis demonstrates that 2/3 of pts receiving baseline transfusions became TI by 6 mo with CNI + EPAG therapy. Most pts received the recommended EPAG dose, were adequately monitored with CNI levels, were able to adhere to treatment and remained on EPAG + CNI for nearly 6 mo. Our findings suggest that CNI + EPAG therapy is feasible and effective in reducing transfusion requirements among pts with AA who are covered by the largest commercial insurance provider in the US.