Clinical outcomes of frontline ATG-based immunosuppressive therapy in older patients with aplastic anemia

Abstract Background Aplastic anemia (AA) exhibits a bimodal age distribution with incidence peaks in young adults and patients aged 60 years. Despite advances in AA management, including the addition of eltrombopag to ATG-cyclosporine and expanded transplant options, older patients remain underrepresented in pivotal ATG-based trials. Age-related comorbidities, reduced stem cell reserve, concerns about treatment tolerance, and frequent ineligibility for stem cell transplantation (SCT) have led to uncertainty about response and long-term outcomes of ATG-based immunosuppressive therapy in this population. Methods We retrospectively analyzed patients ≥60 years receiving ATG-based first-line therapy for AA, comparing those above and below 70 years. NGS-detected benign gene variants were excluded, and no pathogenic germline mutations were identified. Disease severity was defined using bone marrow cellularity 25% and baseline peripheral blood counts as thresholds. RFS was calculated from best response to loss of response or death; OS from treatment initiation to death or last follow-up. Results From 2011 to 2024, 56 patients aged ≥60 years received ATG-based therapy: 26 aged 60-69 years and 30 aged ≥70 years. The median age at diagnosis was 71 (range, 60-85). Fifty-five percent were female. A higher percentage of patients ≥70 had performance status ≥1 (93% vs 72%, p=NS). In both age groups, 73% received eltrombopag together with ATG and cyclosporine. Median hemoglobin, platelets, and WBC at baseline were similar between age groups. The cohort included 29/56 (52%) with non-severe AA, 12/56 (21%) with severe (SAA), and 15/56 (27%) with very severe disease (vSAA). Patients ≥70 years had more SAA and vSAA compared to those 70 (63% vs 40.7%, p=0.025). Two patients 70 years experienced disease transformation. One with refractory AA progressed to AML three months post-diagnosis, while the other achieved CR but developed MDS findings on bone marrow evaluation following count recovery. Two patients underwent SCT for refractory AA. One patient died 9 days post-conditioning due to intracranial hemorrhage, while the second remains in CR at 3 years post-SCT. Gene mutations were detected in 11 patients (18%), most commonly ASXL1 (n=4, 7%), DNMT3A (n=4, 6%), and U2AF1 (n=2, 3.5%), with no significant difference in frequency between age groups. Cytogenetic abnormalities were present in only 2 patients (7%, del(13q) and del(20q)), while conventional karyotype analysis failed in 37% of cases. The overall response rate was 33/56 (59%), with CR achieved in 14/56 (25%) and PR in 19/56 (34%). The OR and CR rates were similar between age groups: 62% (CR 31%) in patients aged 60-69 years versus 57% (CR 20%) in patients ≥70 years (p=0.7 and 0.4 respectively).Eighteen patients (32%) did not respond, and response was not evaluable in 5 patients (9%) due to early death within the first three months (n=4) or loss to follow-up (n=1). The median age of patients with early death was 75.3 years (70.6-81.3). Causes of early death included PRES from CSA, patient-elected palliative care, sepsis, and unknown cause. Among responders, median time to response was 4.2 months (1.7-13.5). In multivariable logistic regression analysis, addition of eltrombopag to ATG and CSA was the only factor that remained significantly associated with response after adjusting for covariates (OR 6.7, p=0.02). At a median follow-up of 35.6 months (95% CI, 20.1-61), the median RFS and OS for the cohort were 32.7 and 55.6 months, respectively. Patients ≥70 years had significantly shorter median RFS and OS (12 and 30.5 months) compared to those 70 years (both not reached, p=0.03). In multivariable Cox regression analysis, after adjusting for covariates including age group, disease severity was the factor most significantly associated with survival, with hazard ratios of 3.8 (1.01-14.2, p=0.04) for SAA and 7.45 (2.4-22.9, p=0.0005) for vSAA. Conclusion Frontline ATG-based IST in older patients with AA is feasible and efficacious with an ORR of 59% and median OS of 55.6 months. The addition of eltrombopag was significantly associated with improved response rates. Early mortality occurred in four patients within the first three months. Disease severity at presentation, rather than age group, was the primary factor associated with survival outcomes.