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Outcome of APL patients after ATO-based treatment
ABSTRACT
The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospec- tive NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P<0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.
Introduction
Acute promyelocytic leukemia (APL), characterized by the balanced translocation t(15;17)(q22;q12) resulting in the fusion transcript PML-RARA, is a rare entity of acute myeloid leukemia, accounting for roughly 5-8% of cases of acute myeloid leukemia.1 With the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), the prog- nosis of APL has been transformed and this is now one of the most curable malignant diseases.
Published data from a large multicenter phase III random- ized trial (APL0406) on a direct comparison of ATO/ATRA versus ATRA in combination with idarubicin (AIDA) or mitoxantrone in adult patients with de novo, low-/interme- diate-risk APL showed very promising results in favor of ATO/ATRA, with a 2-year event-free survival rate of 97% versus 86% (P=0.02).2 Within this trial, the early mortality rate as well as hematologic toxicities were significantly lower in patients treated with ATO/ATRA than in those treated with AIDA. In particular, the cumulative incidence of relapse after 50 months was only 1.9% after ATO/ATRA as compared to 13.9% after chemotherapy and ATRA.3 Moreover, none of the patients treated with ATO/ATRA developed a therapy-related myeloid neoplasm as com- pared to two patients in the chemotherapy/ATRA arm.3 Another Medical Research Council publication supported these results, with a 4-year event-free survival rate of 91% after ATO/ATRA as compared to 70% after chemotherapy and ATRA (P=0.002).4 The ATO/ATRA regimen was, how- ever, associated with a higher frequency of grade 3 or 4 hepatic toxicity (44% vs. 3%; P<0.001). In all cases, toxic effects resolved with temporary discontinuation of ATO and/or ATRA3 and the chemotherapy-free regimen with ATO/ATRA has become standard first-line therapy in low- /intermediate-risk de novo APL. However, apart from reports of the randomized Italian-German APL04062,3 and the AML17 trials,4 data on outcomes after up-front treat- ment with ATO/ATRA in the real-world setting are scarce.
Previously published data from registries and population- based studies indicated that outcomes of patients with APL were inferior to those reported in clinical trials, mainly due to higher early death rates.5-8 However, none of these stud- ies included results after treatment with ATO/ATRA. Recently published results from the randomized Italian-
German APL0406 trial suggest, albeit within the context of highly selected patients and closely monitored therapy, that treatment with ATO/ATRA can reduce early deaths and improve long-term outcomes.2,3 Whether or not these results can be replicated in population-based settings is cur- rently unclear.
The objectives of our study were to characterize a large series of APL patients included in the prospective NAPOLEON registry and evaluate their outcome after up- front treatment with ATO/ATRA.
Methods
Patients and treatment
Data on 167 APL patients, reported within the NAPOLEON registry (ClinicalTrials.gov Identifier: NCT02192619) between 2013 and 2019 within two large European study groups (APL French group, n=89; Study Alliance Leukemia, n=78) were collect- ed. This real-life registry included data on patients’ demographics, treatment, response, severe adverse events and follow-up. There were no criteria for exclusion of APL patients from this registry. However, for the current analysis the inclusion criterion was treat- ment with ATO/ATRA and exclusion criteria were age below 18 years (n=6), high-risk APL (white blood cell [WBC] count >10x109/L, at diagnosis, n=4) and lack of data on WBC count (n=3). The final study cohort consisted of 154 patients. Ideally, patients were included within the same (n=45) or following (n=32) day of APL diagnosis. Additionally 46 patients were included within the first 8 days after diagnosis (overall n=123; 80%), when the risk of early death is highest.8 Outcome was calculated using the date of initial diagnosis. None of the patients was treated within a clinical trial.
The diagnosis of APL was based on genetic analysis as well as on French-American-British Cooperative Group criteria,9 and, after 2003, on revised International Working Group criteria.10 Chromosome banding analysis was performed using standard techniques, and karyotypes were described according to the International System for Human Cytogenetic Nomenclature.11 The diagnosis was confirmed by either reverse-transcriptase poly- merase chain reaction (RT-PCR) or fluorescence in-situ hybridiza- tion (FISH) detection by standard methods. FLT3 mutation screen- ing for internal tandem duplications (ITD) and point mutations within the tyrosine kinase domain was carried out as previously
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