Long-term outcomes of intensive immunosuppressive therapy combined with eltrombopag in patients with severe aplastic anemia

Abstract Background：For severe aplastic anemia (SAA)patients who are ineligible for allogeneic hematopoietic stem cell transplantation (HSCT), the combination of eltrombopag and intensive immunosuppressive therapy (IST) has become the first-line treatment regimen. There are few reports on the long-term outcomes of this regimen.Objective:To investigate the long-term outcomes of patients with SAA treated with ISTcombined with eltrombopag in a real-world, focusing on hematopoietic recovery, disease relapse, and clonal evolution.Methods:A follow-up was conducted on 69 adult SAA patients from May 2014 to October 2021, among whom 34 patients were treated with eltrombopag in combination. The median follow-up duration was 63 (range, 36–118) months. Baseline testing included cytogenetic testing and mutations in genes related to myeloid tumors. Those with abnormalities were tested every 6 months, while those without abnormalities were tested every 12 months.Results:After IST, 89.9% of the patients became transfusion independent. Between the IST alone group and the EPAG group, the cumulative complete response (CR) rates in the ANC were 75.8% vs. 97.0% (P = 0.014), the hemoglobin (HGB) were 70.6% vs. 70.9% (P = 0.851), and the blood platelet count (BPC) were 38.2% vs. 64.5% (P = 0.024), respectively at 5 years of follow-up. Five patients relapsed, with the 5-year cumulative relapse rate was 6.0%, age was positively correlated with the risk of relapse (P = 0.039, HR = 1.06, 95% CI 1.00 to 1.12). One patient had paroxysmal nocturnal hemoglobinuria (PNH) clones detected before treatment, and 11 patients had PNH clones detected after treatment.Chromosomal karyotyping was successfully performed in 23 patients, revealing one patient with add(13)(p11) before treatment. The patient achieved partial remission (PR) receiving IST combined with EPAG.After treatment four patients had chromosomal karyotype abnormalities detected. One patient showed deletion of chromosome 7 (-7), one patient exhibited deletion of chromosome 7 (-7) combined with trisomy of chromosome 2 (+2), one patient presented with trisomy of chromosome 8 (+8), and one patient displayed del(13)(q14). Among these four patients, two carrying -7 (both received IST) experienced disease progression and eventually developed myelodysplastic syndromes (MDS). The remaining two patients achieved CR by IST combined with EPAG.Genetic profiling for myeloid neoplasms was performed in 51 patients, with 23 in EPAG group and 28 in IST alone group. Before treatment, DNMT3A (2 patients), ASXL1 (1 patient), BCOR (1 patient), TP53 (1 patient), MPL (1 patient) were found. After treatment, DNMT3A (7 patients), ASXL1 (6 patients), BCOR /BCORL1(4 patients), RUNX1（3 patients）, TP53 (3 patient) , TET2 （1 patient）, KRAS（1 patient）were found. The rate of gene mutations significantly increased after IST (11.8% vs. 37.3%, P = 0.003). At baseline, the proportion of mutations was comparable between the EPAG group and IST-alone groups (13.0% vs 10.7%, p=0.80). Following treatment, the mutation rates increased to 34.8% and 39.3% in the respective groups (p=0.74).Five patients developed myeloid malignancies. All patients received immunosuppressive therapy (IST) as monotherapy, yet only one achieved PR prior to disease progression. One displayed an isolated -7 aberration, while the other presented with a complex karyotype of -7 combined with +2. Genetic testing identified an ASXL1 mutation in one patient, and another with concurrent RUNX1 and KRAS mutations. The remaining case showed neither cytogenetic nor molecular abnormalities.Conclusion:EPAG could promote the recovery of ANC and BPC. The risk of relapse increases with patient age. EPAG does not increase the risk of progression to myeloid neoplasms in SAA patients treated by IST.