Superiority of anthracycline-free treatment in standard-risk acute promyelocytic leukemia: A systematic review and comparative epidemiological analysis.

BACKGROUND: Recent advances in the treatment of acute promyelocytic leukemia (APML) have seen unprecedented improvements in patient outcomes. However, such rapid growth in understanding often leads to uncertainty regarding superiority among candidate treatment regimens, especially when further scrutinized from an epidemiological perspective. AIMS: The aim of this systematic review with epidemiological analysis was to identify and compare commonly utilized protocols for standard-risk APML with a particular focus on complete remission (CR), overall/disease-free survival (DFS), and reported adverse events. METHODS AND RESULTS: Medline, Scopus, and CINAHL were interrogated to identify studies utilizing all-trans retinoic acid (ATRA) in addition to arsenic trioxide (ATO) and/or anthracyclines such as idarubicin (IDA) in the treatment of de-novo APML. After collation of studies, an epidemiological analysis was subsequently performed to compare protocols with regards to outcomes of interest using number needed to benefit (NNB) and number needed to harm (NNH) measures. Seventeen articles, describing 12 distinct trials, were included in the analysis. These trials made use of three unique protocols; CR rates were 94%-100% for ATO/ATRA regimens, 95%-96% for ATO/ATRA/anthracycline regimens, and 89%-94% for ATRA/anthracycline regimens. Epidemiological analysis demonstrated NNB for CR was 9.09 (ATO/ATRA vs. ATRA/IDA) and 20.00 (ATO/ATRA vs. ATO/ATRA/IDA), NNH for neutropenia was -3.45 (ATO/ATRA vs. ATRA/IDA), and NNH for infection was -3.13 (ATO/ATRA vs. ATRA/IDA) and -1.89 (ATO/ATRA vs. ATO/ATRA/IDA). CONCLUSION: The ATO/ATRA regimen is superior to chemotherapy-containing protocols at inducing remission and promoting survival in patients with APML. The regimen is better tolerated than the proposed alternatives with fewer adverse events. Future research opportunities include quantifying APML epidemiology and pursuing oral arsenic as an option for simplification of therapeutic protocols.

Research on different compound combinations of Realgar-Indigo naturalis formula to reverse acute promyelocytic leukemia arsenic resistance by regulating autophagy through mTOR pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, the Chinese patent drug Realgar-Indigo naturalis Formula (RIF) is utilized for the therapy of acute promyelocytic leukemia (APL). Comprising four traditional Chinese herb-Realgar, Indigo naturalis, Salvia miltiorrhiza, and Pseudostellaria heterophylla-it notably includes tetra-arsenic tetra-sulfide, indirubin, tanshinone IIa, and total saponins of Radix Pseudostellariae as its primary active components. Due to its arsenic content, RIF distinctly contributes to the therapy for APL. However, the challenge of arsenic resistance in APL patients complicates the clinical use of arsenic agents. Interestingly, RIF demonstrates a high remission rate in APL patients, suggesting that its efficacy is not significantly compromised by arsenic resistance. Yet, the current state of research on RIF's ability to reverse arsenic resistance remains unclear. AIM OF THE STUDY: To investigate the mechanism of different combinations of the compound of RIF in reversing arsenic resistance in APL. MATERIALS AND METHODS: The present study utilized the arsenic-resistant HL60-PMLA216V-RARα cell line to investigate the effects of various RIF compounds, namely tetra-arsenic tetra-sulfide (A), indirubin (I), tanshinone IIa (T), and total saponins of Radix Pseudostellariae (S). The assessment of cell viability, observation of cell morphology, and evaluation of cell apoptosis were performed. Furthermore, the mitochondrial membrane potential, changes in the levels of PMLA216V-RARα, apoptosis-related factors, and the PI3K/AKT/mTOR pathway were examined, along with autophagy in all experimental groups. Meanwhile, we observed the changes about autophagy after blocking the PI3K or mTOR pathway. RESULTS: Tanshinone IIa, indirubin and total saponins of Radix Pseudostellariae could enhance the effect of tetra-arsenic tetra-sulfide down-regulating PMLA216V-RARα, and the mechanism was suggested to be related to inhibiting mTOR pathway to activate autophagy. CONCLUSIONS: We illustrated that the synergistic effect of different compound combinations of RIF can regulate autophagy through the mTOR pathway, enhance cell apoptosis, and degrade arsenic-resistant PMLA216V-RARα.

Clinical Indicators of Hepatotoxicity in Newly Diagnosed Acute Promyelocytic Leukemia Patients Undergoing Arsenic Trioxide Treatment.

Arsenic trioxide (ATO)-induced hepatotoxicity is often observed in acute promyelocytic leukemia (APL) patients and decreases therapeutic effect of ATO. Thus, concerns over hepatotoxicity have been raised. The aim of this study was to explore some noninvasive clinical indicators that can be used to guide the individualized application of ATO in the future. APL patients treated with ATO were identified retrospectively via electronic health records at our hospital from August 2014 through August 2019. APL patients without hepatotoxicity were selected as controls. The association between putative risk factors and ATO-induced hepatotoxicity was estimated with ORs and 95% CIs, which were calculated using the chi-square test. The subsequent multivariate analysis was performed using logistic regression analysis. In total, 58.04% of patients experienced ATO-induced hepatotoxicity during the first week. Elevated hemoglobin (OR 8.653, 95% CI, 1.339-55.921), administration of nonprophylactic hepatoprotective agents (OR 36.455, 95% CI, 7.409-179.364), non-single-agent ATO to combat leukocytosis (OR 20.108, 95% CI, 1.357-297.893) and decreased fibrinogen (OR 3.496, 95% CI, 1.127-10.846) were found to be statistically significant risk factors for ATO-induced hepatotoxicity. The area under the ROC curve values were 0.846 for "overall ATO-induced hepatotoxicity" and 0.819 for "early ATO-induced hepatotoxicity." The results revealed that hemoglobin ≥ 80 g/L, nonprophylactic hepatoprotective agents, and non-single-agent ATO and fibrinogen < 1 g/L are risk factors for ATO-induced hepatotoxicity in newly diagnosed APL patients. These findings can enhance the clinical diagnosis of hepatotoxicity. Prospective studies should be performed in the future to validate these findings.

Arsenic trioxide: applications, mechanisms of action, toxicity and rescue strategies to date.

Arsenical medicine has obtained its status in traditional Chinese medicine for more than 2,000 years. In the 1970s, arsenic trioxide was identified to have high efficacy and potency for the treatment of acute promyelocytic leukemia, which promoted many studies on the therapeutic effects of arsenic trioxide. Currently, arsenic trioxide is widely used to treat acute promyelocytic leukemia and various solid tumors through various mechanisms of action in clinical practice; however, it is accompanied by a series of adverse reactions, especially cardiac toxicity. This review presents a comprehensive overview of arsenic trioxide from preclinical and clinical efficacy, potential mechanisms of action, toxicities, and rescue strategies for toxicities to provide guidance or assistance for the clinical application of arsenic trioxide.

Estimation of the Frequency and Time of Human Exposure to Arsenic by Single Hair Analysis.

Arsenic (As) and its compounds are widely used in many applications. Long-term exposure to As can cause acute and chronic poisoning. In severe cases, it can lead to adverse effects, such as gene mutation, cell cancer and fetal malformation. The objective of this study was to accurately estimate As exposure frequency and time. Quantitative analysis of As in single hairs obtained from APL (acute promyelocytic leukemia) patients treated with As2O3 was performed by LA-ICP-MS. An informative As concentration distribution profile of single hair was applied to estimate the As exposure frequency and time. As exposure frequency was estimated according to the number of As concentration peaks. As exposure time was estimated according to the hair growth length in combination with the hair growth rate. The validation results demonstrate that this method was more efficient than the traditional method; compared with the traditional method, which provides estimates in months, our model shortened the As exposure time estimate to the range of a few days, which considerably improved the inference accuracy. Therefore, these results can be used for forensic toxicology studies, environmental exposure monitoring, etc.

Successful Treatment of Therapy-related Acute Promyelocytic Leukemia with All-trans-retinoic acid Following Epirubicin for Hepatocellular Carcinoma and Docetaxel and Pembrolizumab Therapies for Lung Carcinoma: A Triple Malignancy Case.

A 69-year-old man was referred to the hematology department for the evaluation of pancytopenia. He had been treated with radiation and epirubicin for hepatocellular carcinoma, and with docetaxel and pembrolizumab for lung adenocarcinoma. Bone marrow smears exhibited markedly increased promyelocytes, and polymerase chain reaction (PCR) study demonstrated chimeric fusion genes of PML-RARA. He was diagnosed with therapy-related acute promyelocytic leukemia (t-APL) and treated with all trans-retinoic acid (ATRA). After 30 days of ATRA treatment, complete hematological response was achieved. To the best of our knowledge, this case represents the first description of successfully treated t-APL diagnosed after treatment with pembrolizumab.

PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis.

Arsenic is a naturally occurring, ubiquitous metalloid found in the Earth's crust. In its inorganic form, arsenic is highly toxic and carcinogenic and is widely found across the globe and throughout the environment. As an International Agency for Research on Cancer-defined class 1 human carcinogen, arsenic can cause multiple human cancers, including liver, lung, urinary bladder, skin, kidney, and prostate. Mechanisms of arsenic-induced carcinogenesis remain elusive, and this review focuses specifically on the role of the PI3K/AKT/mTOR pathway in promoting cancer development. In addition to exerting potent carcinogenic responses, arsenic is also known for its therapeutic effects against acute promyelocytic leukemia. Current literature suggests that arsenic can achieve both therapeutic as well as carcinogenic effects, and this review serves to examine the paradoxical effects of arsenic, specifically through the PI3K/AKT/mTOR pathway. Furthermore, a comprehensive review of current literature reveals an imperative need for future studies to establish and pinpoint the exact conditions for which arsenic can, and through what mechanisms it is able to, differentially regulate the PI3K/AKT/mTOR pathway to maximize the therapeutic and minimize the carcinogenic properties of arsenic.

Lentivirus­mediated RIG­I knockdown relieves cell proliferation inhibition, cell cycle arrest and apoptosis in ATRA­induced NB4 cells via the AKT­FOXO3A signaling pathway in vitro.

Retinoic acid inducible gene I (RIG­I) is upregulated during all­trans retinoic acid (ATRA)­induced terminal granulocytic differentiation of NB4 acute promyelocytic leukemia (APL) cells. However, the function and mechanism of RIG­I in NB4 cells remains to be fully elucidated. In the present study, lentivirus­mediated RIG­I­knockdown was used to investigate the proliferation, cell cycle and apoptotic processes of ATRA­induced NB4 cells in vitro using an MTT assay and flow cytometry, respectively. The roles of RIG­I and the AKT­FOXO3A signaling pathway were investigated using western blot analysis. The results showed that the ATRA­induced expression of RIG­I was specifically and effectively knocked down at the mRNA and protein levels by lentivirus mediated RIG­I short hairpin RNA. In addition, silencing of RIG­I reduced the ATRA­induced inhibition of NB4 cell proliferation, cell cycle arrest and apoptosis. Further investigations indicated that with ATRA­induced expression of RIG­I, levels of phosphorylated (p)AKT­Thr308 and pForkhead Box (FOX) O3A­Thr32 were decreased, the expression levels of cell cycle arrest protein p27 and the apoptotic protein, tumor necrosis factor­related apoptosis­inducing ligand (TRAIL), directly transcribed by FOXO3A were increased. By contrast, following the knockdown of ATRA­induced expression of RIG­I, the levels of pAKT­Thr308 and pFOXO3A­Thr32 were increased, and the protein expression levels of p27 and TRAIL were decreased. Taken together, these results showed that the knockdown of RIG­I reduced the inhibition of cell proliferation, cell cycle arrest and apoptosis in the ATRA­induced NB4 cells via the AKT­FOXO3A signaling pathway.

[Acute Promyelocytic Leukemia Developed during Imatinib Therapy for Gastrointestinal Stromal Tumors].

OBJECTIVE: To investigate the clinicopathologic and molecular characteristics of acute promyelocytic leukemia(APL) developed during imatinib therapy for gastrointestinal stromal tumors(GIST). METHODS: A 49-year-old woman was hospitalized for abdominal pain. The abdominal CT revealed a gastric mass. Laparoscopic resection of the tumor was performed. The histopathologic analysis showed poorly differentiated malignant cell infiltration with epithelioid features. Immunohistochemistry staining of these cells was positive for CD117 and CD34. GIST was confirmed and imatinib treatment was given. RESULTS: After 1 year,the patient developed progressive pancytopenia. Bone marrow aspirate showed marked hyperplasia of bone marrow cells with 92.5% promyelocyte, consistent with APL. Cytogenetic analysis demonstrated t(15;17)(q22;q21) as the sole abnormality. PML/RARα fusion gene was positive and Kit mutation was negative. After combined treatment with ATRA, arsenic trioxide and idarubicin, patient achieved cytogenetic and molecular remission. CONCLUSION: The metachronous coexistence of GIST with APL is uncommon. The potential nonrandom association and causal relationship between these malignancies remained to be investigated. Further studies would be necessary to clarify the relationship between imatinib and secondary malignancies in GIST patients.

Secondary acute promyelocytic leukemia following chemotherapy for gastric cancer: a case report.

Therapy-related acute myeloid leukemia (t-AML) refers to a heterogeneous group of myeloid neoplasms that develop in patients following extensive exposure to either cytotoxic agents or radiation. The development of t-AML has been reported following treatment of cancers ranging from hematological malignancies to solid tumors; however, to our knowledge, t-AML has never been reported following treatment of gastric cancer. In this study, we report the development of t-acute promyelocytic leukemia in a cT4N1M0 gastric cancer patient after an approximate 44 mo latency period following treatment with 4 cycles of oxaliplatin (OXP) (85 mg/m(2) on day 1) plus capecitabine (1250 mg/m(2) orally twice daily on days 1-14) in combination with recombinant human granulocyte-colony stimulating factor treatment. Karyotype analysis of the patient revealed 46,XY,t(15;17)(q22;q21)[15]/46,idem,-9,+add(9)(p22)[2]/46,XY[3], which, according to previous studies, includes some "favorable" genetic abnormalities. The patient was then treated with all-trans retinoic acid (ATRA, 25 mg/m(2)/d) plus arsenic trioxide (ATO, 10 mg/d) and attained complete remission. Our case illuminated the role of certain cytotoxic agents in the induction of t-AML following gastric cancer treatment. We recommend instituting a mandatory additional evaluation for patients undergoing these therapies in the future.

Late onset post-transfusion hepatitis E developing during chemotherapy for acute promyelocytic leukemia.

We herein report the case of a leukemia patient who developed hepatitis E seven months after undergoing a transfusion with contaminated blood products. The latency period in this case was significantly longer than that of typical hepatitis E. Recently, chronic infection with hepatitis E virus (HEV) genotype 3 has been reported in immunocompromised patients. There is a possibility that our patient was unable to eliminate the virus due to immunosuppression following chemotherapy and the administration of steroids. The prevalence of HEV in healthy Japanese individuals is relatively high and constitutes a critical source of infection via transfusion. Hepatitis E is an important post-transfusion infection, and immunocompromised patients may exhibit a long latency period before developing the disease.

Global characteristics of childhood acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) comprises approximately 5-10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning >60 countries) identified, variation was apparent-de novo APL represented from 2% (Switzerland) to >50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed.

Acute promyelocytic leukaemia (APL) in a patient with Crohn's disease and exposure to infliximab: a rare clinical presentation and review of the literature.

With the introduction of potent immunosuppressive and chemotherapeutic medications for various diseases, there is an increased incidence of therapy-related myeloid neoplasms. They are the result of mutational rearrangement and historically, have a grave prognosis compared with de novo myeloid neoplasms. We did a short review on various types of myeloid leukaemias reported after therapy with antitumour necrosis factor and also report, to the best of our knowledge, one among the very few cases of therapy-related acute promyelocytic leukaemia in a patient on infliximab therapy for refractory Crohn's disease. The patient responded well to the traditional treatment and is in complete remission for more than 5 years.

Therapy-related acute promyelocytic leukemia following etoposide-based chemotherapy in non-seminomatous germ cell tumor.

Therapy related AML (t- AML) accounts for 10-20% of all cases of AML. Cytotoxic agents implicated are alkylating agents, topoisomerase II inhibitors and rarely anti metabolites and anti tubulin agents. A growing incidence of therapy related acute promyelocytic leukemia (t-APL) has been reported over the last few decades in malignant and non malignant conditions. To the best of our knowledge this is the first t-APL case report to be reported in NSGCT post etoposide based therapy.

Effect of myeloperoxidase inhibition on gene expression profiles in HL-60 cells exposed to 1,2,4,-benzenetriol.

While it is known that benzene induces myeloid leukemia in humans, the mechanism has yet to be clarified. Previously, we suggested that myeloperoxidase (MPO) was the key enzyme because it promotes generation of powerful oxidant hypochlorous acid (HOCl) which, reacting with DNA, causes leukemogenesis. In this study, using a whole-human-genome oligonucleotide microarray to clarify the relationships between myelotoxicity of benzene and MPO, we analyzed the genome-wide expression profiles of HL-60 human promyelocytic cell lines exposed to 1,2,4-benzenetriol (BT) with or without MPO inhibition. The microarray analysis revealed that short (1 h) and longer (4 h) exposure to BT changed the expression in HL-60 cells of 1,213 or 1,214 genes associated with transcription, RNA metabolic processes, immune response, apoptosis, cell death, and biosynthetic processes (|Z-score|> 2.0), and that these changes were dramatically lessened by MPO-specific inhibition. The presence of functionally important genes and, specifically, genes related to apoptosis, carcinogenesis, regulation of transcription, immune responses, oxidative stress, and cell-cycle regulation were further validated by real-time RT-PCR. Gene expression profiles along with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation analysis suggest that BT-induced DNA halogenation by MPO is a primary reaction in the leukemogenesis associated with benzene.

Arsenic. Can this toxic metalloid sustain life?

It was recently reported that a bacterium, Halomonas species GFAJ-1, isolated from arsenic-rich Mono Lake and further selected for growth under conditions of high arsenate and low phosphate, is able to grow using arsenic instead of phosphorus. This claim, and subsequent studies to evaluate GFAJ-1, has brought new attention to the question of whether arsenic can play an essential or sustaining role for living organisms. If true, this would be in stark contrast to the well known toxicity of this element and its ability to cause a number of diseases, including cancer of the skin, lung, bladder, liver, and kidney. However, while deadly at high doses, arsenic oxide is also an approved and effective chemotherapeutic drug for the treatment of acute promyelocytic leukemia (APL). This review examines the evidence that arsenic may be a beneficial nutrient at trace levels below the background to which living organisms are normally exposed. It also examines whether arsenic can be used to sustain organisms growing under high arsenic conditions, specifically the results from recent studies of arsenic biochemistry motivated by the report of GFAJ-1. Both of these topics are considered in the context of the toxicity of this element and its ability to cause cancer and other diseases, yet its Janus-faced ability to effectively treat APL.

[Report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature].

OBJECTIVE: To explore the characteristics and risk of etoposide-related leukemia in the treatment of hemophagocytic lymphohistiocytosis (HLH). METHOD: Clinical characteristics of a case with secondary acute promyelocytic leukemia (APL) were summarized and 10 cases of secondary leukemia after treatment for HLH from literature were analyzed. RESULT: The child was diagnosed with Epstein-Barr virus associated HLH and received HLH-2004 protocol. The cumulative dose of etoposide (VP16) was 3520 mg/m(2). The patient was diagnosed with APL after 28 months of HLH.He achieved complete remission after induction chemotherapy of all-trans-retinoic acid and darubicin. Consolidated chemotherapy was continued. There were 10 reports of etoposide-related leukemia after treatment for HLH in the literature.Review of 11 cases treated with VP16, of which cumulative doses were 900-20 500 mg/m(2). The interval period between HLH and secondary leukemia was 24 months. The types of secondary leukemia included 1 case with acute lymphoblastic leukemia, 1 case with myelodysplastic syndrome and 9 cases of acute myeloid leukemia. The abnormalities of chromosome included 3 patients with 11q23, 3 APL patients with t (15, 17).Seven patients survived and 4 died. CONCLUSION: The latency period of etoposide-related leukemia is short. Acute myeloid leukemia and balanced chromosomal abnormality are common in etoposide-related leukemia. The risk factors for development of secondary leukemia are related to cumulative drug doses of etoposide, treatment schedules and co-administration of other antineoplastic agents.It is appropriate to keep suitable range of the cumulative dose of etoposide in HLH therapy in order to reduce the risk of therapy related leukemia.