Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid– and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.

To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on clinical experience. Nearly 100,000 formulae have been recorded, but the working mechanisms of most remain unknown. In trying to address the possible beneficial effects of formulae with current biomedical approaches, we use Realgar-Indigo naturalis formula (RIF), which has been proven to be very effective in treating human acute promyelocytic leukemia (APL) as a model. The main components of RIF are realgar, Indigo naturalis, and Salvia miltiorrhiza, with tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T) as major active ingredients, respectively. Here, we report that the ATI combination yields synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro. ATI causes intensified ubiquitination/degradation of promyelocytic leukemia (PML)-retinoic acid receptor ␣ (RAR␣) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G1/G0 arrest in APL cells through hitting multiple targets compared with the effects of mono-or biagents. Furthermore, ATI intensifies the expression of Aquaglyceroporin 9 and facilitates the transportation of A into APL cells, which in turn enhances A-mediated PML-RAR␣ degradation and therapeutic efficacy. Our data also indicate A as the principal component of the formula, whereas T and I serve as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae at the molecular, cellular, and organism levels may be a good strategy in exploring the value of traditional medicine.traditional chinese medicine ͉ active ingredient ͉ tetraarsenic tetrasulfide ͉ synergism ͉ systems biology T he complexity of medicine suggests that treatment protocols should be carefully designed, and the construction of a prescription is an art in fighting disease. Increasing evidence demonstrates that, in treating illnesses, including cancer (1) and HIV/AIDS (2), treatment regimens containing multiple drugs with distinct but related mechanisms can usually amplify the therapeutic efficacies of each agent, leading to maximal therapeutic efficacy with minimal adverse effects. Interestingly, combination therapy has been advocated for Ͼ2,500 years by prescriptions called formulae (3, 4) in traditional Chinese medicine (TCM), a unique medical system assisting the ancient Chinese in dealing with disease. Typically, formulae consist of several types of medicinal herbs or minerals, in which one represents the principal component, and others serve as adjuvant ones to assist the effects or facilitate the delivery of the principal component (3, 4). It is believed that, at least in some formulae, multiple components could hit multiple targets and exert synergistic therapeutic efficacies (3, 4). However, essential compounds have not been identified in most formulae, whereas precise mechanisms of form...

We have identified a unique case of acute promyelocytic leukaemia (APL) with a t(11;17) reciprocal chromosomal translocation involving the retinoic acid receptor alpha (RAR alpha) and a previously uncharacterized zinc finger gene. As a result of this translocation, mRNAs containing the coding sequences of the new gene, fused in‐frame either upstream of the RAR alpha B region or downstream from the unique A1 and A2 regions of the two major RAR alpha isoforms, are expressed from the rearranged alleles. The above gene, which we have termed PLZF (for promyelocytic leukaemia zinc finger), encodes a potential transcription factor containing nine zinc finger motifs related to the Drosophila gap gene Krüppel and is expressed as at least two isoforms which differ in the sequences encoding the N‐terminal region of the protein. Within the haematopoietic system the PLZF mRNAs were detected in the bone marrow, early myeloid cell lines and peripheral blood mononuclear cells, but not in lymphoid cell lines or tissues. In addition, the PLZF mRNA levels were down‐regulated in NB‐4 and HL‐60 promyelocytic cell lines in response to retinoic acid‐induced granulocytic differentiation and were very low in mature granulocytes. Our results demonstrate for the first time the association of a variant chromosomal translocation involving the RAR alpha gene with APL, further implicating the RAR alpha in leukaemogenesis and also suggesting an important role for PLZF as well as retinoic acid and its receptors in myeloid maturation.

All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combinationbased therapy has benefitted newly diagnosed acute promyelocytic leukemia (APL) in short-term studies, but the long-term efficacy and safety remained unclear. From April 2001, we have followed 85 patients administrated ATRA/ATO with a median follow-up of 70 months. Eighty patients (94.1%) entered complete remission (CR). Kaplan-Meier estimates of the 5-year event-free survival (EFS) and overall survival (OS) for all patients were 89.2% ؎ 3.4% and 91.7% ؎ 3.0%, respectively, and the 5-year relapse-free survival (RFS) and OS for patients who achieved CR (n ‫؍‬ 80) were 94.8% ؎ 2.5% and 97.4% ؎ 1.8%, respectively. Upon ATRA/ATO, prognosis was not influenced by initial white blood cell count, distinct PML-RAR␣ types, or FLT3 mutations. The toxicity profile was mild and reversible. No secondary carcinoma was observed, and 24 months after the last dose of ATRA/ATO, patients had urine arsenic concentrations well below the safety limit. These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for de novo APL.combination therapy ͉ 5-year EFS ͉ 5-year OS ͉ residual disease ͉ arsenic retention A cute promyelocytic leukemia (APL) is the M3 subtype of acute myeloid leukemia (AML) and is characterized by an accumulation of abnormal promyelocytes in the bone marrow and a severe bleeding tendency. Additionally, in the great majority of cases, APL is associated with the t(15,17) chromosomal translocation and resultant PML-RAR␣ transcripts that encode the leukemogenic PML-RAR␣ fusion protein (1). Five decades ago, APL was the most fatal type of acute leukemia and was considered essentially untreatable (2). The first breakthrough came with the use of anthracyclines, which improved the complete remission (CR) rate but provided a low 5-year overall survival (OS) (3). The introduction of all-trans retinoic acid (ATRA) therapy resulted in terminal differentiation of APL cells and a 90-95% CR rate in patients (1, 4), and subsequent combination of ATRA with chemotherapy raised the 5-year disease-free survival (DFS) rate up to 74% (5). In the 1990s, significant benefits of arsenic trioxide (ATO) were reported, which further improved the outcome of patients with APL (6, 7). ATO exerts dose-dependent dual effects on APL cells, with low concentrations inducing partial differentiation and relatively high concentrations triggering apoptosis. Of note, both ATRA and ATO induce catabolism of the PML-RAR␣ fusion protein, demonstrating a paradigm for rationally targeted therapy in leukemia. However, between 20% and 30% of newly diagnosed APL patients treated with regimens based on the use of ATRA or ATO as single agents will develop disease recurrence or drug resistance.To improve further the clinical outcome of APL, therapeutic strategies should be designed to include combinatorial use of drugs with distinct but convergent mechanisms that may amplify treatment effic...