Long-Term Follow-Up Confirms the Benefit of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (As2O3) as Front Line Therapy for Newly Diagnosed Acute Promyelocytic Leukemia (APL).
Authors: Liu Yuan-Fang , Zhu Yong-Mei , Shi Zhan-Zhong , Li Jun-Min , Wang Li , Chen Yu , Shen Zhi-Xiang , Hu Jiong 
Published: October 2019

Abstract
PURPOSE: To further confirm the benifit of front-line use of all-trans retinoic acid (ATRA) combined with arsenic trioxide (As2O3) in patients with newly diagnosed acute promyelocytic leukemia (APL), we observed the long-term survival of the current group (median follow-up: 48 months) and compared it with our historical control.
PATIENTS AND METHODS: There were two groups of patients with newly diagnosed APL enrolled in this analysis. The current cohort of patients includes 60 patients since April 2001. The historical cohort of patients included 56 patients from May 1998 to March 2001. No statistically significant differences were found between these two groups in terms of clinical characteristics including sex and age distribution or hematological data before treatment. For the current cohort of patients, all patients received 25mg/m2 ATRA orally and 0.16mg/kg As2O3 intravenously per day till CR. Once CR achieved, they were given 3 courses of consolidation chemotherapy and then 5 cycles of sequential treatment of ATRA, As2O3 and 6-MP/MTX. For the historical group, ATRA was given either 25mg/m2 daily till CR, chemotherapy was added in case of leukocytosis. The post-remission therapy consists of chemotherapy with or without ATRA. Quantitative real-time reverse transcription-polymerase chain reaction (RQ-RT-PCR) measurements of PML-RARa mRNA were retrospectively assessed before treatment, after CR, after consolidation, after maintenance and during follow-up period. The efficacy of these two protocol in terms of remission induction, molecular response and long-term survival were compared with our historical control. RESULT: In the current group, 56 (93.3%) patients achieved CR, and the median time to CR was 27 days. Compared with the historical group, the combined therapy induced an early hematological response. Till the last follow-up at April 2006, two patients underwent extramedullary relapse, one of them also relapsed in marrow thereafter, one patient died from CNS leukemia, and all the other patients were alive and remained in hematological remission. With a median follow-up of 48 months (25 to 60 months), the 4-year OS and EFS was estimated 98.1%±1.8% and 94.2%±3.3%. For the historical group, after a median follow-up of 56 months (12 to 79 months), the 4-year OS and EFS was estimated 83.4%±5.4% (P=0.012) and 45.6%±7.6% (P<0.00001). For the current group, PML-RARa normalized dose was more significantly decreased after remission induction and after consolidation as compared with the historical cohort. In the last follow-up, all of the available event-free patients of the current group remain in molecular remission (PML-RARa DoseN undetectable). CONCLUSION: These 4-year data of follow-up demonstated a benefit of front-line combination of ATRA and As2O3 regarding long-term survival (OS or EFS) of patients with newly diagnosed APL. With prolonged follow-up, we might be able to find a better chance of curing the disease.