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Autophagy: New Insights into Mechanisms of Action and Resistance of Treatment in Acute Promyelocytic leukemia.
Moosavi, MA, Djavaheri-Mergny, M
International journal of molecular sciences. 2019;(14)
Abstract
Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all-trans retinoid acid (ATRA)-a differentiating agent currently used in clinical settings-restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL.
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[Acute promyelocytic leukemia with stat5b- RARα fusiongene: a case report and literatures review].
Liu, L, Chen, S, Tan, J, Shi, P, Chen, K, Gao, D, Huang, X, Xie, Y, Xu, Y, Yang, F, et al
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2016;(1):68-9
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Contemporary treatment of APL.
Cull, EH, Altman, JK
Current hematologic malignancy reports. 2014;(2):193-201
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Abstract
Acute promyelocytic leukemia (APL) is characterized by coagulopathy, leukopenic presentation and sensitivity to anthracyclines, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). For the last 25 years, APL has been treated with a combination of ATRA and chemotherapy for induction followed by consolidation and maintenance therapy. This general treatment approach has resulted in cure rates of 80-90 %. ATO, originally approved in relapsed APL, has been incorporated into contemporary upfront treatment regimens with excellent response rates. Recent studies show that most patients with APL can be cured with ATRA and ATO alone, eliminating cytotoxic chemotherapy and resulting in superior outcomes compared to standard treatment. We will herein review historical treatment of APL, treatment considerations in specific patient populations, and therapeutic updates.
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How I treat children and adolescents with acute promyelocytic leukaemia.
Abla, O, Ribeiro, RC
British journal of haematology. 2014;(1):24-38
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Abstract
Acute promyelocytic leukaemia (APL) is a rare subtype of acute myeloid leukaemia. The outcome of paediatric APL has improved substantially over the past 20 years; cure rates above 80% are expected when all-trans retinoic acid (ATRA) is given with anthracycline-based regimens. The presenting features of paediatric APL may include severe bleeding and thrombotic complications, which contribute to the high early death rate. The incidence of leucocytosis and the microgranular subtype is greater in paediatric than adult APL, and children experience greater ATRA-related toxicity. It is crucial to begin ATRA therapy and intensive platelet and fibrinogen replacement on first suspicion of APL. Recent risk-adapted therapeutic trials have shown that patients at greater risk of relapse benefit from the introduction of high-dose cytarabine during consolidation. Combination therapy with ATRA and arsenic trioxide provides very effective frontline treatment and may reduce the need for subsequent anthracycline therapy.
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The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia.
Breen, KA, Grimwade, D, Hunt, BJ
British journal of haematology. 2012;(1):24-36
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Abstract
Coagulopathy occurs in most patients with (APML) and is life-threatening; therefore prompt diagnosis and recognition of any coagulation defect is imperative. Unfortunately haemorrhage remains a major cause of early death, preventing some from reaching treatment. The coagulopathy is caused directly or indirectly by the leukaemic cells through expression of activators of coagulation and fibrinolysis, proteases and cytokine generation, compounded by failure of platelet production due to marrow invasion. At presentation the predominant feature is usually hyperfibrinolysis. Since the introduction of all-trans retinoic acid (ATRA), patient outcome has dramatically improved; yet, haemorrhagic complications remain the most frequent cause of mortality. Thrombotic complications occur but are less well recognized and potentially underreported. Supportive measures and prompt initiation of ATRA currently represent the mainstay of treatment of the coagulopathy in patients with suspected APML, but unanswered questions remain as to the optimal approach to further decrease the associated haemorrhagic and thrombotic risks. In particular, it is unclear how to best predict and monitor the coagulopathy; whether there is a role for the early use of antifibrinolytics; the most appropriate trigger for giving fibrinogen replacement and the value of low-dose anticoagulation to suppress coagulation activation once fibrinolysis has been suppressed.
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Treatment of acute promyelocytic leukemia without cytotoxic chemotherapy.
Park, JH, Tallman, MS
Oncology (Williston Park, N.Y.). 2011;(8):733-41
Abstract
The introduction of all-trans retinoic acid, or ATRA, in 1985, combined with anthracycline-based chemotherapy, has transformed acute promyelocytic leukemia (APL) from a fatal disease to one that is now highly curable. With appropriate contemporary therapy, more than 90% of patients achieve complete remission, and cure rates of approximately 80% and higher response and survival rates can be expected for patients at low and intermediate risk. The introduction of arsenic trioxide, or ATO, in 1994 has provided the opportunity to minimize and even eliminate standard cytotoxic chemotherapy from initial treatment regimens without compromising the excellent outcomes achieved by anthracycline-containing protocols. APL is a unique subtype of acute myeloid leukemia that is curable with targeted therapies and potentially without exposure to conventional DNA-damaging chemotherapy. The omission of conventional cytotoxic chemotherapy may reduce long-term complications such as cardiomyopathy and therapy-related myelodysplastic syndromes. Cure rates of APL may be further increased by adopting management strategies to reduce early hemorrhagic deaths, which now appear to be the major cause of treatment failure.
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Acute promyelocytic leukemia can be treated successfully without cytotoxic chemotherapy.
Ravandi, F
Oncology (Williston Park, N.Y.). 2011;(8):741-3
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Curing all patients with acute promyelocytic leukemia: are we there yet?
Baljevic, M, Park, JH, Stein, E, Douer, D, Altman, JK, Tallman, MS
Hematology/oncology clinics of North America. 2011;(6):1215-33, viii
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Abstract
The introduction of all-trans retinoic acid to anthracycline-based chemotherapy has revolutionized the prognosis of patients with acute promyelocytic leukemia (APL). The introduction of arsenic trioxide enabled the therapeutic approach of rationally targeted frontline protocols with minimal or no traditional cytotoxic chemotherapy and without compromise of previously established outstanding outcomes with anthracycline-based regimens. Although most of the current investigative efforts in APL are focused on developing potentially curative therapy without the exposure to toxicities and risks of DNA-disrupting agents, the cure rate can further be increased by implementing meticulous supportive care strategies that counter early coagulopathy-related deaths.
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Arsenic trioxide - An old drug rediscovered.
Emadi, A, Gore, SD
Blood reviews. 2010;(4-5):191-9
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Abstract
Over the last 17 years, clinical trials conducted worldwide have demonstrated the efficacy of arsenic trioxide (As(2)O(3)) in the treatment of relapsed acute promyelocytic leukemia (APL). Currently, the role of As(2)O(3) in front-line therapy is under investigation. Recent trials in the US have demonstrated that the addition of As(2)O(3) to standard treatment regimens improves survival outcomes in patients with APL and may allow a reduction in cytotoxic chemotherapy exposure. As(2)O(3) has also shown efficacy in other malignancies, particularly multiple myeloma and myelodysplastic syndromes. Therapeutic doses of As(2)O(3) are well tolerated, with no evidence of long-term toxicity. Adverse events include APL differentiation syndrome, electrocardiographic abnormalities, and mild elevations in liver enzymes. This review highlights trials investigating the role of As(2)O(3) in induction and consolidation for newly diagnosed APL, as well as its role in other hematologic malignancies. The chemistry, mechanisms of action, and clinical side effects of As(2)O(3) are also discussed.
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2. All-trans retinoic acid in the treatment of acute promyelocytic leukemia.
Asou, N
Internal medicine (Tokyo, Japan). 2007;(2):91-3