Improved Real-World Outcomes of Patients with Acute Promyelocytic Leukemia Treated with First-Line Arsenic Trioxide in Specialized Centers in Portugal through a 24/7 Phone-Based Referral: A Study from the Portuguese Acute Leukemia Group

Introduction Acute Promyelocytic Leukemia (APL) has evolved from the most lethal into the most curable acute leukemia today, due to targeted treatments such as all-transretinoic acid (ATRA) plus arsenic trioxide (ATO). First-line ATO was adopted in 2017 in Portugal, where APL is exclusively treated in University Hospitals after a 24/7 phone-based referral from community centers made doctor-to-doctor. It is unknown whether the outcomes of patients receiving ATRA + ATO in Portugal mirror the excellent clinical trial results, and if early death (ED) rates have been improved from the pre-ATO era in the country. Methods We conducted an observational, retrospective and multicenter study, including 5 University Hospitals in Portugal. All patients with genetically confirmed APL who received first-line ATO plus ATRA between January 2017 and May 2024 were included, regardless of disease risk. Induction response assessment and molecular measurable residual disease (MRD) monitoring using real-time quantitative PCR were performed as per ELN guidelines. Results A total of 135 patients were included in the study, with a median age of 50 years (range 18-82); 16.3% of patients were over 70 years of age, but only 4.4% had an ECOG performance status ≥2. This cohort was composed mostly of non-high risk APL (92.6%), while 10 patients with high-risk APL received ATO due to contraindications for anthracyclines or age >70 years. Seventy-nine patients (58.5%) first presented to a community hospital and were transferred to the closest APL-treating hospital following a phone contact. The median time between APL suspicion and treatment initiation was 1 day (range 0-14). The 30-day early death (ED) rate was 3.7%, attributable to intracranial bleeding (n=3) and septic shock (n=2). Age was the only statistically significant predictor of ED (OR 1.1 [95%CI 1.0-1.2], p=0.028), with age >75 years increasing the odds of ED 8.9 times (p=0.025). The most frequent complications during ATRA + ATO treatment were febrile neutropenia (75%), bleeding (18.5%), differentiation syndrome (DS) (17.7%) and hepatotoxicity (14.1%). The incidence rate of DS was significantly lower in the 118 patients who received corticosteroid prophylaxis (14.4%) than in the 17 patients who did not (41.1%). Among the 125 patients evaluable for marrow response, 100% achieved hematologic complete response (CR). All the 101 patients who completed the 4 consolidation courses achieved negative molecular MRD. Regarding the role of ATO in high-risk patients, 9/10 patients in our cohort achieved hematological complete response (1 succumbed to ED), and all the 4 patients who completed treatment at study cut-off date achieved negative MRD. With a median follow-up of 33.4 months, the median overall survival (OS) was not reached. The 2-year OS rate was 94.0%, and there was only 1 APL relapse during the study follow-up. Discussion In the setting of centralized APL care using a fast nationwide referral method, our real-world results compare favourably with the APL-0406 clinical trial outcomes. We validate the universal achievement of CR in those who survived induction, and of negative MRD in all who completed therapy. The higher ED rate in our study probably reflects an older, unselected population, whereas APL-0406 excluded patients over 71 years of age. Despite low numbers, our data support the universal use of DS prophylaxis and first-line ATO's applicability in high-risk patients, who also benefited from this regimen. Through quick initiation of treatment with the effective ATRA + ATO combination, we showed a considerable improvement in the ED rate in 2017-2024, which is a third of the 11.4% ED rate previously reported by our group in a non-high risk APL cohort treated with ATRA + chemotherapy from 2010 to 2017.