Outcomes with ATO/ATRA based regimen in apml - steroid induced toxicities are a concern in LMICs

Abstract

Abstract Background: ATO/ATRA forms the backbone of induction therapy in the treatment of APML. However, its use is frequently associated with differentiation syndrome, prompting the use of prophylactic steroids. Prolonged steroid use in the Indian setting could be harmful due to the higher risk of fungal and multi-drug bacterial infections. In line with this, the present study was conducted to study the complications associated with the use of ATO/ATRA protocol in our setting. Methods This retrospective single-center study was conducted on the data extracted from the APML registry database maintained for an IEC approved and CTRI registered study (CTRI/2020/02/023455). The analysis included APML patients aged >15 years treated between 2013–2018. Patients were stratified by Sanz risk criteria (low/intermediate vs. high risk). Low/intermediate-risk patients received ATRA and ATO; high-risk patients received ATRA/ATO plus chemotherapy. The primary endpoint was the incidence of steroid-associated complications such as infections and hyperglycemia. Secondary endpoints included Event-Free Survival (EFS), Overall Survival (OS), and induction mortality. Results A total of 149 patients were included (mean age 36 ± 13 years, 60.4% male), 110 received ATRA/ATO with or without chemotherapy (study cohort) and 39 received ATRA and ATO alone. In the study cohort, 80% were low-intermediate risk and 88.1% achieved complete remission following induction. Induction mortality was 5.45% (6/110), and were due to infections (n=3), coagulopathy (n=1), and differentiation syndrome (n=2). Among 110 patients, 83 were started on steroids either prophylactic or for the treatment of differentiation syndrome. Among the 83 patients who received steroids, 11 (13.2%) developed hyperglycemia. Fungal infections were documented in 18 patients (21.7%), of which 12 (66.6%) were classified as possible, 5 (27.7%) as probable, and 1 (5.5%) as proven infection. Bloodstream bacterial infections were identified in 9 patients (10.8%), 5 with gram-negative organisms and 4 with gram-positive organisms. On analysis of 83 patients who received steroids, the steroid use was not associated with increased fungal infections (p=0.724), but was linked to higher hyperglycemia rates (p = 0.021). The 6-year survival probability was 90.6% (95% CI: 0.851 - 0.961) and Event Free Survival was 78.4% (95% CI: 0.704 - 0.864). The 6-year EFS by Sanz risk was 86.5% for low-risk, 80.4% for intermediate-risk, and 72.2% for high-risk patients; however, no statistically significant difference in survival was observed between the risk groups (p = 0.636). Treatment-related toxicities included hepatotoxicity in 26.6%, neurotoxicity in 6.3%, and QTc prolongation in 0.8%; most were manageable, with no toxicity-related deaths. Relapses occurred in 6.36% (medullary: 57.1%, CNS: 14.2%, both: 28.5%). Conclusion APML remains a highly treatable form of acute leukemia, with contemporary induction protocols significantly reducing early mortality and achieving favorable long-term survival across risk groups. The frequent occurrence of differentiation syndrome and the metabolic complications associated with steroid use highlights the need for careful clinical monitoring and improved supportive care.