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Acute promyelocytic leukemia: from highly fatal to highly curable
1Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Riu Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai, China. xiejx@publicsta2.sta.net.cn
Abstract:
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia. Morphologically, it is identified as the M3 subtype of acute myeloid leukemia by the French-American-British classification and cytogenetically is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between promyelocytic leukemia (PML) gene and retinoic acid receptor alpha (RARalpha). It seems that the disease is the most malignant form of acute leukemia with a severe bleeding tendency and a fatal course of only weeks. Chemotherapy (CT; daunorubicin, idarubicin and cytosine arabinoside) was the front-line treatment of APL with a complete remission (CR) rate of 75% to 80% in newly diagnosed patients. Despite all these progresses, the median duration of remission ranged from 11 to 25 months and only 35% to 45% of the patients could be cured by CT. Since the introduction of all-trans retinoic acid (ATRA) in the treatment and optimization of the ATRA-based regimens, the CR rate was raised up to 90% to 95% and 5-year disease free survival (DFS) to 74%. The use of arsenic trioxide (ATO) since early 1990s further improved the clinical outcome of refractory or relapsed as well as newly diagnosed APL. In this article, we review the history of introduction of ATRA and ATO into clinical use and the mechanistic studies in understanding this model of cancer targeted therapy.
Insights
Acute promyelocytic leukemia (APL), a severe leukemia subtype, has seen improved outcomes with targeted therapies. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) significantly increase remission rates and survival for APL patients.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Acute promyelocytic leukemia (APL) is a highly aggressive subtype of acute myeloid leukemia (AML).
- APL is characterized by a specific chromosomal translocation t(15;17) involving the PML and RARalpha genes.
- Historically, chemotherapy offered limited cure rates for APL, with a high risk of bleeding and rapid fatality.
Observation:
- Chemotherapy (CT) achieved complete remission (CR) in 75-80% of newly diagnosed APL patients, but long-term survival was poor.
- Median remission duration with CT was 11-25 months, with only 35-45% of patients cured.
- The introduction of all-trans retinoic acid (ATRA) revolutionized APL treatment.
Findings:
- ATRA-based regimens increased CR rates to 90-95% and 5-year disease-free survival (DFS) to 74%.
- Arsenic trioxide (ATO) further improved outcomes for both newly diagnosed and relapsed/refractory APL.
- Combined ATRA and ATO represent a highly effective targeted therapy for APL.
Implications:
- APL serves as a paradigm for targeted cancer therapy, demonstrating the power of understanding molecular mechanisms.
- ATRA and ATO have transformed APL from a fatal disease to a curable one for most patients.
- Further research into the mechanisms of ATRA and ATO can inform other cancer treatments.
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