Prognostic consequences of delayed treatment in severe aplastic anemia: A challenge in resource-constrained healthcare systems

Abstract Introduction:In aplastic anemia(AA), hematologic response is the strongest predictor of overall survival(OS). However, disparities in healthcare access often led to treatment delays, resulting in two major consequences: multiple infections and excessive transfusion requirements. Our objective was to determine the referral time associated with better overall response rates(ORR), and describe availability of diagnostic and treatment resources for AA in Mexico. Methods:We conducted a multicenter retrospective study including patients diagnosed with AA between 1975 and 2025 from six tertiary care centers. We described social characteristics, diagnostic tool availability, and access to treatment. Overall response rate(ORR) was defined as the sum of complete response(CR), and partial response(PR). Responses were assessed at 3 and 6 months.Time intervals were defined as follows:•Care-seeking time:from symptom onset to first medical contact.•Referral time:from first medical contact to arrival at the referral center.• Diagnostic time:from arrival at referral center to definitive diagnosis.•Symptom-to-treatment time:from symptom onset to treatment initiation.• Time to transplantation:from diagnosis to hematopoietic stem cell transplantation (HSCT). Results:A total 260 patients with severe(SAA) or very severe aplastic anemia(VSAA) were identified. At diagnosis, 132 were male(50.8%) with a median age of 40 years(IQR 21–57). A total of 71 patients(27.7%) had a low level of education(up to complete elementary school), 128(50%) had a medium level(complete middle school or high school), and 57(22.3%) had a high level of education(at least complete a university major). Before diagnosis, 164 patients(63.1%) were employed and suspended work due to the diagnosis of AA. Due to limitations in healthcare access, karyotype was not performed in 131 patients(50.4%), PNH clone testing in 207(79.6%), and 225(86.5%) were not evaluated by a Geneticist.First-line treatment was received by 129 patients(49.6%). Among them, 39(15%) received HSCT, 98(37.7%) received an ATG-based regimen, and 121(46.5%) received immunosuppressive therapy without ATG. Horse ATG was available for only 3 patients(1.2%).Sixty-one patients(23.5%) achieved OR at 3 months, and 102patients(39.2%) at 6, regardless of treatment type.HSCT was performed in 44 patients(16.9%) at any moment duringfollow-up.Median time intervals were as folows: referral time,35.1 days(IQR10–90.6); diagnostic time, 33.9 days(IQR 14.01–75.6); symptom-to-treatment time, 3.37 months(IQR1.98-6.2);and time to transplantation, 8.88 months(IQR4.87–23.1).Patients who achieved ORR had shorter referral time(0.66 months;IQR0.1–0.27vs1.27months;IQR0.46–3.55,p=0.011),symptom-to-treatment time(1.4 months;IQR0.78–3.58vs2.15 months;IQR1.03–4.31,p=0.068), and time to transplantation(13.1 months;IQR5.37–23.8vs16.9 months;IQR9.52–43.1,p=0.0003). No difference in OS was found in patients that received HSCT(p=0.085). The analysis for education level and global treatment response revealed relevant differences. At 3 months, there was a tendency in significance(p=0.051) for response rates:7.8% of patients with a high level of education responded, compared to only 4.7% in the low education group and 11.3% in the medium group. At 6 months, results were statistically significant (p<0.001),demonstrating a clear association between educational level and global response, given that a favorable response was seen in 12.9% of patients with high education, compared to 5.9% with low education and 21.1% with medium education. Discussion and Conclusions:Overall response rates in our population are lower than those reported internationally(60% at 3 months).Contributing factors include that 50% of patients did not receive adequate first-line treatment, horse ATG was used in only 1.2%, and access to diagnostic tools was severely limited. Notably, HSCT did not result in better OS, likely due to significantly to an extended time to transplantation.Our findings show that reducing referral time from primary to tertiary centers and expediting treatment initiation, including HSCT, is crucial for improving ORR.Additionally, educational level, a key socioeconomic factor that remains challenging to address systematically, was associated with poorer outcomes. Enhancing access to diagnostic tools and therapies, and ideally improving educational attainment, will be essential to optimize survival and overall prognosis in patients with AA in our country.