How to Manage Acute Promyelocytic Leukemia

Leukemia (2012) 26, 1743 -- 1751 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu HOW TO MANAGEy How to manage acute promyelocytic leukemia J-Q Mi, J-M Li, Z-X Shen, S-J Chen and Z Chen Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL is changing, from the worst among AML as it used to be, to currently the best. The application of all-trans-retinoic acid (ATRA) to the induction therapy of APL decreases the mortality of newly diagnosed patients, thereby significantly improving the response rate. Therefore, ATRA combined with anthracycline-based chemotherapy has been widely accepted and used as a classic treatment. It has been demonstrated that high doses of cytarabine have a good effect on the prevention of relapse for high-risk patients. However, as the indications of arsenic trioxide (ATO) for APL are being extended from the original relapse treatment to the first-line treatment of de novo APL, we find that the regimen of ATRA, combined with ATO, seems to be a new treatment option because of their targeting mechanisms, milder toxicities and improvements of long-term outcomes; this combination may become a potentially curable treatment modality for APL. We discuss the therapeutic strategies for APL, particularly the novel approaches to newly diagnosed patients and the handling of side effects of treatment and relapse treatment, so as to ensure each newly diagnosed patient of APL the most timely and best treatment. Leukemia (2012) 26, 1743--1751; doi:10.1038/leu.2012.57 Keywords: acute promyelocytic leukemia (APL); all-trans-retinoic acid (ATRA); arsenic trioxide (ATO) INTRODUCTION In this review, we introduce the therapeutic strategies of APL, Acute promyelocytic leukemia (APL) is a distinct subtype of acute including the treatment of newly diagnosed and relapsed myeloid leukemia (AML) characterized by its abnormal promye- patients, as well as the ways to deal with the side effects. locytes infiltrating bone marrow and other hematopoietic organs In addition, we show a novel paradigm of translational medicine and its t(15;17) translocation leading to PML--RARa fusion gene. here. The experimental and clinical researches have promoted and There have been tremendous innovations in therapeutic strategies inspired each other, which has led to a revolution in the treatment and substantial improvement in the outcome of patients since the of leukemia. application of all-trans-retinoic acid (ATRA).1 The leukemia cells undergo terminal differentiation under the remission induction of ATRA, in contrast to cytolysis with conventional chemotherapy, LEUKEMOGENESIS OF APL AND MECHANISMS UNDERLYING which ameliorate the coagulopathy, thereby reducing the EFFECT OF ATRA/ATO requirement of blood products and the difficulty of initial More than 98% of APL patients harbor t(15;17) in leukemia cells,7 treatment. This effect has been particularly evident in developing which results in the fusion of RARa on chromosome 17 to PML on countries, due to the limitations of medical resources. At present, chromosome 15.8 The consequence is the generation of the ATRA combined with chemotherapy became the classic treatment PML--RARa fusion gene encoding a chimeric protein. APL has a of APL owing to the significantly improved long-term survival rate. nearly constant incidence with age, suggesting that it arises from The further amelioration of chemotherapy in the past two a single rate-limiting genetic event and PML--RARa is the constant decades, for example, the application of high-dose cytosine genomic abnormality in APL cells.9 Transgenic mice with arabinoside to high-risk patients2,3 and the recognition of the PML--RARa develop a typical APL phenotype.10,11 These findings importance of maintenance therapy,4 has led to further improve- in addition to other evidence have established PML--RARa as the ment of APL survival.5 However, it has always been our dream to key driver of APL leukemogenesis. lower the relapse rate and to reduce side effects through even PML--RARa protein is an abnormal transcriptional factor, more effective therapy targeting APL cells. The use of arsenic retaining N-terminal RBCC (RING, B Boxes and coiled coil) domains trioxide (ATO) in the last two decades, from salvage therapy for of PML and most portions of RARa.12 PML--RARa expression is relapsed cases to the first-line therapy,6 gradually revealed its believed to exert a dominant-negative dual-function on each of its superiority in the treatment of APL, proven by a sizable proportion parental proteins, which are demonstrated to be involved in of patients cured by just a single agent as the compound directly various cellular processes such as myeloid differentiation, apop- targets PML--RARa. Moreover, a great majority of patients tosis and DNA replication and repair.13 Several crucial PML--RARa achieved a 5-year disease-free survival when treated with the features contribute to APL pathogenesis, such as the absolute combination of ATO and ATRA. Therefore, the association of ATO binding with RXRa,14 -- 16 interaction with the chromatin remodel- and ATRA5 is gradually being accepted by all. We have confidence ing complexes17 -- 19 and functional disruption of other key in the hope that it will become a new standard treatment for APL, myeloid transcription factors (that is, PU.1).20 In addition, other although the results of randomised comparisons are still being genetic alterations are present such as mutations in NRAS, awaited. KRAS, FLT3--internal tandem duplication (FLT3--ITD) and point State Key Laboratory for Medical Genomics and Department of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Correspondence: Dr J-Q Mi or Dr Z Chen, State Key Laboratory for Medical Genomics and Department of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai 200025, China. E-mail: [email protected] (J-QM) or [email protected] (ZC) Received 24 August 2011; revised 20 February 2012; accepted 21 February 2012; accepted article preview online 16 March 2012; advance online publication, 30 March 2012 APL and its treatment J-Q Mi et al 1744 mutations of FLT3--tyrosine kinase domain (FLT3--TKD) as well as intermediate risk (WBC count o10 Â 109/l, platelet count Jak1,21 -- 23 which favor APL progression in patients. p40 Â 109/l) and high risk (WBC count X10 Â 109/l).39 Although The critical role of PML--RARa in APL leukemogenesis has also it is reported from time to time that CD56 expression in patients suggested itself as a potential target for APL treatment. Indeed, with APL may be an independent factor predicting poor PML--RARa represents the direct pharmaceutical target of two prognosis, further confirmation is needed.40,41 effective agents for APL, ATRA and ATO (Figure 1a). Arsenic binds We agree with the views of Sanz et al.42 that three simultaneous to the RBCC domain of PML moiety,24,25 whereas ATRA targets the actions should be done when a diagnosis of APL is suspected: the RARa moiety of PML--RARa. Both the agents can induce the start of ATRA therapy before confirmation of the diagnosis; degradation of PML--RARa,26 -- 29 which probably accounts for institution of supportive measures; and rapid confirmation of their curable effects. genetic diagnosis. As Tallman et al.5 mentioned, bleeding is the Leukemia-initiating cells (LICs) are a rare subpopulation in the most dangerous complication and represents a major cause of bulk of leukemia, which are pluripotent, self-renewing and early death (ED) for the newly diagnosed APL patients. When APL mitotically quiescent, and responsible for the development, is highly suspected with clinical symptoms such as peripheral progression and maintenance of leukemia.30 The non-cycling blood smear and bone marrow morphology, it’s not necessary to status and inherent or acquired drug-resistant feature of LICs wait for the confirmation by cytogenetic or molecular studies. make them insensitive to conventional chemotherapy, that could Immediate application of ATRA would be a wise choice, so that the explain the later relapse of leukemia. Although nearly all the APL biological signs of APL coagulopathy could be improved rapidly, patients could obtain complete remission using ATRA or ATO as a decreasing the risk of severe bleeding. For the high-risk patients single agent, most single ATRA-treated cases would relapse, with hyperleukocytosis (for example, WBC410 Â 109/l), once the contrarily to the situation of ATO, which could cure a sizable diagnosis is confirmed, chemotherapy should be initiated as soon portion (around 65%) of the patients,31 -- 33 suggesting that ATO as possible (immediately or be delayed for up to 1 day) to prevent targets the LICs in APL (Figure 1b). More recently, the targeted serious APL differentiation syndrome (DS). clearance of LICs by arsenic treatment has been reported in Supportive measures are particularly important in the first few mouse models.34,35 Besides PML--RARa, a number of proteins days after the beginning of APL treatment, especially for those have been described to have an important role in the counteracting the coagulopathy. Although severe bleedings can maintenance of LICs phenotype, many of which, indeed, have be significantly controlled with the use of ATRA, we still encounter been shown to be targeted by arsenic, including PML,35 Gli2(ref. 36) a small number of patients being on the verge of death when they and NFkB.37 However, ATRA has been reported to exert a dual come to seek treatment, with chief complaints being serious effect on LICs: induction of differentiation in the more mature bleedings.43 It must be emphasized that every positive effort blast population and induction of proliferation and/or self-renewal should be made, both in detection and in treatment.

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