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Acute promyelocytic leukemia (APL), a distinctive subtype of acute myeloid leukemia (AML), is characterized by the t(15; 17) translocation forming the PML-RARα fusion protein. Recent studies have revealed a crucial role of retinoid X receptor α (RXRα) in PML-RARα's tumorigenesis. This necessitates the development of dual RARα and RXRα targeting compounds for treating APL. Here, we developed a pair of brominated retinoid isomers, 5a and 5b, exhibiting RARα agonistic selectivity among the RAR subtypes and RXRα partial agonistic activities. In the treatment of APL cells, low doses (RARα activation range) of 5a and 5b degrade PML-RARα and strongly induce differentiation, while higher doses (RXRα activation range) induce G 2 /M arrest and apoptosis in both all-trans retinoic acid (ATRA)-sensitive and resistant cells. We replaced the bromine in 5a with chlorine or iodine to obtain compounds 7 or 8a. Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G 2 /M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The treatment of acute promyelocytic leukemia (APL) has evolved with the introduction of all-trans retinoic acid (ATRA) and subsequent arsenic trioxide (ATO), particularly in standard-risk APL with an initial white blood cell count (WBC) < 10,000/μL, where a high cure rate can now be achieved. However, for some patients with risk factors, early death or relapse remains a concern. Insights from the analysis of patients treated with ATRA and chemotherapy have identified risk factors such as WBC, surface antigens, complex karyotypes, FLT3 and other genetic mutations, p73 isoforms, variant rearrangements, and drug resistance mutations. However, in the ATRA + ATO era, the significance of these risk factors is changing. This article provides a comprehensive review of APL risk factors, taking into account the treatment approach, and explores the challenges associated with APL treatments., (© 2024. Japanese Society of Hematology.)

Rationale: Acute myeloid leukemia with NPM1, IDH2, and SETD2 mutations can mimic acute promyelocytic leukemia (APL) and poses a challenge for the early and accurate differentiation and diagnosis of APL with PML::RARA., Patient Concerns: A 70-year-old man was diagnosed with acute myeloid leukemia with NPM1, IDH2, and SETD2 mutations., Diagnosis: APL-like acute myeloid leukemia with NPM1, IDH2, and SETD2 mutations was made., Interventions: The patient received all-trans retinoic acid 20 mg 3 times a day for 22 days, azacitidine 100 mg subcutaneously once daily for 7 days, and venetoclax 100 mg once daily for 12 days., Outcomes: Due to economical constraints, the patient stopped further treatment, and outcome was dismal., Lessons: The comprehensive evaluation of bone marrow morphology, immunology, cytogenetics, and molecular biology is essential for the accurate diagnosis of acute myeloid leukemia., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

In acute promyelocytic leukemia (APL), the combination treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) appears to have a synergistic effect. Due to this synergism, differentiation syndrome (DS) in APL assumes a distinct identity separate from the formerly known ATRA syndrome, with distinct temporal patterns, diagnostic parameters, and clinical behavior. We retrospectively evaluated single-center data of years 2013-2022. Patients with newly diagnosed APL were categorized into three groups (16 patients in ATRA/ATO standard-risk group, 3 patients in ATRA/chemotherapy standard-risk group, and 5 patients in ATRA/chemotherapy high-risk group). Our aim was to analyze leukocytosis, signs of DS, and hepatic impairment within the first 25 days of treatment. The incidence of DS in the ATRA/ATO SR group was 43.8 %, with a median of 4 days and 2 days from ATRA and ATO initiation, respectively. This group also exhibited higher peak levels of leukocytosis 34.5 (6.0-113.4) x10 9 /L (p = 0.0809). ALT elevation was more prevalent in the ATRA/ATO SR group (93.75 %), with 68.75 % grade 3-4 elevations (p = 0.0094). Importantly, all patients in this group had ALT levels that returned to normal during the subsequent consolidations. These findings suggest hepatopathy as a potential manifestation of ATRA/ATO induced leukocyte differentiation and/or DS. Diverse differentiation patterns were identified within the ATRA/ATO group, classifying patients into three distinct subgroups based on the concurrent dynamics of leukocytes and ALT levels, illustrating simultaneous, sequential, and divergent elevation patterns. These emphasize the different distribution of differentiation (organs vs. peripheral blood). We introduced real-world data and advocated for reevaluation of the current DS definition and associated diagnostic thresholds. Our study, conducted in a small country with a limited number of APL patients, acknowledges the inherent constraints in sample size. Further investigations with larger patient cohorts are warranted to validate and reinforce the outcomes observed in our study., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Acute promyelocytic leukemia (APL) is a distinct form of acute myeloid leukemia characterized by the presence of t(15;17)(q24;21) and the PML:RARA gene fusion. Frontline use of intravenous arsenic trioxide (i.v.-ATO) and all-trans retinoic acid (ATRA) has vastly improved cure rates in APL. Researchers in Hong Kong invented the oral formulation of ATO (oral-ATO) and have confirmed a bioavailability comparable to i.v.-ATO. A plethora of studies have confirmed the safety and efficacy of oral-ATO-based regimens in the frontline and relapsed setting., Areas Covered: Aspects on the development of oral-ATO-based regimens for APL in the frontline and relapsed setting are discussed. The short-term and long-term safety and efficacy of oral-ATO-based regimens are discussed. The frontline use of oral-ATO in combination with ATRA and ascorbic acid (AAA) induction in a 'chemotherapy-free' is highlighted., Expert Opinion: Current and ongoing data on the use of oral-ATO-based regimens in APL support the use of oral-ATO as an alternative to i.v.-ATO allowing a more convenient and economical approach to the management of APL.

Differentiation syndrome (DS) is the second leading cause of death in acute promyelocytic leukaemia (APL) patients. Few studies have tested predictors of DS events. This study aimed to identify optimized predictors of DS events related to APL. The data of 298 consecutive patients who were newly diagnosed with APL between December 2012 and June 2023 were retrospectively investigated. A systematic review of computer-based patient medical records was conducted to obtain clinical data, including baseline characteristics, routine blood examination findings, biochemical indices and clinical manifestations of DS. Among the 298 patients, 158 were classified into the no-DS group, while 140 had DS. Compared with those of patients without DS, the peripheral blast count, age, and WBC count at each time point were significantly different in patients with DS (P < 0.05 for all time points). Generalized linear mixed models (GLMMs) revealed that WBC Double (Coeff. 0.442, P = 0.000) and WBC Peak (Coeff. 0.879, P = 0.000) were independent risk factors for DS. The frequencies of clinical manifestations of unexplained fever (P = 0.003), dyspnoea (P = 0.002), weight gain of more than 5 kg (P = 0.006), pleural effusion (P = 0.001), pulmonary infiltrates (P < 0.001), pericardial effusion (P = 0.002) and renal failure (P = 0.006) were considerably lower in moderate DS patients than in severe DS patients. The WBC Double occurs earlier than the WBC peak occurrence, so WBC  Double might be a new indicator of DS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Liver injury during arsenic treatment for acute promyelocytic leukemia was previously reported in adults, but not comprehensively in children until now. This study aims to investigate liver injury in pediatric patients with APL, changes in liver function during treatment, and compare the effects of Arsenic trioxide (ATO) and Realgar-Indigo naturalis formula (RIF) on liver function. One hundred and eighty-six patients with 3076 patient tests were analyzed, who were enrolled in the Chinese Children's Leukemia Group (CCLG)-APL2016 Protocol database between November 2016 and November 2018 in 38 hospitals across China(ChiCTR-OIN-17011227). Twenty of 164 patients (12.2%) suffered from liver injury after treatment with arsenic. In addition, sixteen (80%) cases of liver injury occurred during the induction period of treatment. What's not disheartening was that 18 (90%) cases of liver injury were transient, occurring at a median time of 17 days after exposure to arsenic. More importantly, the risk of liver injury associated with RIF was not higher than that associated with ATO (RR = 0.854, 95% CI: 0.292-2.495). Otherwise, the ALP of 18 cases of liver injury was not higher than the ULN of ALP. Thus, the incidence of liver injury associated with arsenic in pediatric patients with APL was similar to that in adult patients and the risk of liver injury associated with RIF was not higher than that associated with ATO. Since ALP was not higher in pediatric APL patients with liver injury, further research is needed to explore whether ALP is an index of liver injury in children., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Acute promyelocytic leukemia (APL) is the sub-type of Acute myeloid leukemia (AML) which is described by differentiation block at promyelocytic stage and t(15; 17) translocation with All trans retinoic acid (ATRA) and arsenic trioxide (ATO) as standard treatments. Chronic myeloid leukemia (CML) translocation t (19; 22) causes a rise in granulocytes and their immature precursors in the blood. Different mutations cause resistance to first-line tyrosine kinase therapies in CML. Beside drug resistance, leukemia stem cells (LSC) are critical resources for relapse and resistance in APL and CML. The drug toxicity and resistant profile associated with LSC and current therapeutics of APL and CML necessitate the development of new therapies. Imidazoles are heterocyclic nitrogen compounds with diverse cellular actions. The purpose of this research was to assess the anti-leukemic properties of four novel imidazole derivatives including L-4, L-7, R-35, and R-NIM04., Methods and Results: Pharmacological and biochemical approaches were used which showed that all four imidazole derivatives interfere with the NB4 cells proliferation, an APL cell line, while only L-7 exhibit anti-proliferative activity against K562 cells, a CML cell line. The anti-proliferative effect of imidazole derivatives was linked to apoptosis induction. Further real-time polymerase chain reaction (RT-PCR) analysis revealed downregulation of AXL-Receptor Tyrosine Kinase (AXL-RTK) and target genes of Wnt/beta-catenin pathway like c-Myc, Axin2 and EYA3. An additive effect was observed after combinatorial treatment of L-7 with standard drugs ATRA or Imatinib on the proliferation of NB4 and K562 cells respectively which was related to further downregulation of target genes of Wnt/beta catenin pathway., Conclusion: Imidazole derivatives significantly reduce proliferation of NB4 and K562 cells by inducing apoptosis, down regulating of AXL-RTK and Wnt/β-catenin target genes., (© 2024. The Author(s).)

Drug resistance is one of the major obstacles to the clinical use of doxorubicin, an extensively used chemotherapeutic drug to treat various cancers, including leukemia. Inhibition of the nuclear factor erythroid 2-related factor 2 (NRF2) seems a promising strategy to reverse chemoresistance in cancer cells. NRF2 is a transcription factor that regulates both antioxidant defense and drug detoxification mechanisms. In this study, we investigated the potential of three inhibitors of NRF2-K67, retinoic acid and ML-385-to overcome doxorubicin resistance in promyelocytic leukemia HL-60 cells. For this purpose, low-dose doxorubicin was used to establish doxorubicin-resistant HL-60/DR cells. The expression of NRF2 and its main repressor, Kelch-like ECH-associated protein 1 (KEAP1), at mRNA and protein levels was examined. HL-60/DR cells overexpressed NRF2 at mRNA and protein levels and down-regulated KEAP1 protein compared to drug-sensitive HL-60 cells. The effects of NRF2 inhibitors on doxorubicin-resistant HL-60/DR cell viability, apoptosis, and intracellular reactive oxygen species (ROS) levels were analyzed. We observed that NRF2 inhibitors significantly sensitized doxorubicin-resistant HL-60/DR cells to doxorubicin, which was associated with increased intracellular ROS levels and the expression of CAS-9 , suggesting the participation of the mitochondrial-dependent apoptosis pathway. Furthermore, ML-385 inhibitor was used to study the expression of NRF2-KEAP1 pathway genes. NRF2 gene and protein expression remained unchanged; however, we noted the down-regulation of KEAP1 protein upon ML-385 treatment. Additionally, the expression of NRF2-regulated antioxidant and detoxification genes including SOD2 , HMOX2 , and GSS was maintained upon ML-385 treatment. In conclusion, our results demonstrated that all the studied inhibitors, namely K67, retinoic acid, and ML-385, increased the efficacy of doxorubicin in doxorubicin-resistant HL-60/DR cells, and suggested a potential strategy of combination therapy using NRF2 inhibitors and doxorubicin in overcoming doxorubicin resistance in leukemia.

Abstract: The introduction of all-trans retinoic acid combined with anthracyclines has significantly improved the outcomes for patients diagnosed with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries in which arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly because of high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the International Consortium on Acute Promyelocytic Leukemia study involving 806 patients with APL recruited from 2005 to 2020 in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has notably decreased to 14.6% compared with the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age of ≥40 years, Eastern Cooperative Oncology Group performance status score of 3, high-risk status based on the Programa Español de Tratamiento en Hematologia/Gruppo Italiano Malattie EMatologiche dell'Adulto classification, albumin level of ≤3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival rate is 81%, the 4-year disease-free survival rate is 80%, and the 4-year cumulative incidence of relapse rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)/retinoic acid receptor α (RARA) fusion oncoprotein. Over the years, it has emerged as a model system to understand how this simple (and sometimes sole) genetic alteration can transform hematopoietic progenitors through the acquisition of dominant-negative properties toward both transcriptional control by nuclear receptors and PML-mediated senescence. The fortuitous identification of two drugs, arsenic trioxide (ATO) and all- trans -retinoic acid (ATRA), that respectively bind PML and RARA to initiate PML/RARA degradation, has allowed an unprecedented dissection of the cellular and molecular mechanisms involved in patients' cure by the ATO/ATRA combination. This analysis has unraveled the dual and complementary roles of RARA and PML in both APL initiation and cure by the ATRA/ATO combination. We discuss how some of the features unraveled by APL studies may be more broadly applicable to some other forms of leukemia. In particular, the functional synergy between drugs that promote differentiation and those that initiate apoptosis/senescence to impede self-renewal could pave the way to novel curative combinations., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Objective: To investigate the relationship between the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and glycolysis, as well as its underlying molecular mechanism., Methods: The GEO database was used to analyze alterations in the expression of RPL22L1 in APL patients and its correlation with glycolysis. The levels of RPL22L1 and glycolysis were assessed in 9 paired clinical samples. NB4 cells and NB4 cells with knockdown of RPL22L1 were treated with ATO. The protein and mRNA of RPL22L1 were detected using RT-PCR and Western blot, and the content was determined by using glucose, pyruvate, and lactate detection kits. Finally, detection of cell proliferation using CCK8, migration by scratch assay, and apoptosis by flow cytometry, and the biological function of ATO in NB4 cells was examined., Results: The expression of RPL22L1 in GSE213742 and GSE234103 datasets exhibited a significant increase in human APL cells, specifically NB4 cells. RPL22L1 in GSE213742 and GSE234103 gene expression matrix was significantly elevated in human APL cells NB4 cells, and further analysis found RPL22L1 showed a strong positive correlation with glycolysis. Cellular experiments showed that ATO inhibited RPL22L1 in NB4 cells and inhibited glycolysis in APL cells. The ATO played a pivotal role in suppressing the proliferation, migration, as well as invasion of NH4 cells., Conclusion: ATO regulates the blycolytic pathway in APL by inhibiting RPL22L1 expression, and this may contribute to its therapeutic effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: There is currently no standard treatment for relapsed and arsenic trioxide (ATO)-resistant acute promyelocytic leukemia (APL). Here, we report a case series of realgar-indigo naturalis formula (RIF) for the successful treatment of patients with relapsed and ATO-resistant APL., Case Presentation: Two patients in the first relapse and one in the second relapse failed to achieve hematologic complete remission (HCR) when reinduced by ATO; the other five patients progressed to relapse during ATO-based regimens for post-remission therapy. These eight patients received RIF in three doses per day totaling 130 mg/kg (≤ 30 pills) as induction therapy and achieved HCR at a median time of 46.5 days. They received 5 years of post-remission therapy, which consisted of combined chemotherapy followed by RIF. During this period, the patients did not experience renal dysfunction or QT interval prolongation. At the last follow-up, three patients survived without relapse, two patients survived with a second or third relapse and third or fourth remission, and the other three patients relapsed for a third or fourth time and died. The 5-year overall survival and event-free survival rates were 75.0% (95% confidence interval [CI]: 31.5-93.1) and 37.5% (95% CI: 5.6-71.7), respectively., Conclusion: RIF for induction therapy and RIF combined with chemotherapy for post-remission therapy may represent an effective and safe protocol for the treatment of patients with relapsed and ATO-resistant APL. Please cite this article as: Fang YG, Huang SL, Chen NN. Realgar-indigo naturalis formula for the treatment of patients with relapsed and arsenic trioxide-resistant acute promyelocytic leukemia: a case series. J Integr Med. 2024; 22(5): 614-620., (Copyright © 2024 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

The objective of this study is to explore the possibility of treating APL patients fully as outpatients. A total of 21 consecutive APL patients were identified over 30 years in the Centro de Hematología y Medicina Interna de Puebla, at Clínica Ruiz, but only 17 were studied, treated as outpatients, and followed for at least 1 month; they were observed for median of 95 months, their median age was 27 years and all were treated with ATRA, prednisone, and adriamycin as outpatients. Treatment was completed on an outpatient basis in 15/17 cases. Molecular remission was achieved in 16/17 patients. The median follow-up was 95 months (IQR 19 - 360). The median OS and LFS were not reached, and the 12-month LFS was 94%. We have confirmed that APL can be treated entirely on an outpatient basis: this observation is of utmost relevance in a resource-limited setting, such as those prevailing in low- and middle-income countries.

Introduction: Acute promyelocytic leukemia (APL) is mainly due to the chromosome translocation t (15; 17) (q22; q12), leading to the formation of PML-RARα fusion protein. However, some patients carried rare translocation involving RARα gene, and they were referred to as variant APL caused by the RAR family (RARα, RARB, and RARG) and partner genes. PLZF-RARα was a rare type of molecular genetic abnormality with unfavorable prognosis that has been reported in few cases in variant APL. Knowledge of PLZF-RARα (+) APL treatment remains limited understood., Case Report: We presented a case of variant APL in a 47-year-old female, who was PLZF-RARα positive detected by reverse transcription polymerase chain reaction (RT-PCR). The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As 2 O 3 ) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative., Conclusion: Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.

Objectives: In patients with acute promyelocytic leukemia (APL), additional chromosomal abnormalities (ACAs) are prognostic indicators. However, the clinical features of ACAs were not systematically reported in Chinese patients. Therefore, we enrolled a large cohort of APLs to demonstrate the clinical characteristics and prognostic value of ACAs., Methods: 268 patients with newly diagnosed APL with t(15;17)(q24;q21) were retrospectively enrolled, and their clinical characteristics and the predictive value of ACAs were assessed between patients with the presence and absence of ACAs., Results: APL patients with and without ACAs did not differ significantly in their clinical features or treatment response and clinical outcomes like overall survival (OS) and disease-free survival (DFS). It appeared to be substantially associated with worse OS in APL patients with trisomy 8, which was the most common ACA, although DFS was unaffected. Interestingly, the presence of ACAs or trisomy 8 affected OS and DFS in the subgroup of patients aged ≥60 years; by contrast, ACAs had no effect on OS or DFS in any treatment subgroup (ATRA + ATO/RIF or ATRA + ATO/RIF + CH or ATRA + CH), except for the ATRA + ATO/RIF + CH treatment subgroup, where their impact on DFS was less favorable., Conclusions: Our results suggested that OS and DFS were unaffected by ACAs. Nonetheless, in the subgroup of patients older than 60, the existence of ACAs or trisomy 8 appeared to impact OS and DFS negatively. Individuals with t(15;17) alone had a higher DFS and were more susceptible to ATRA + ATO/RIF + CH than individuals with t(15;17) ACAs.

Promyelocytic leukemia (PML) nuclear bodies, membrane-less organelles in the nucleus, play a crucial role in cellular homeostasis. These dynamic structures result from the assembly of scaffolding PML proteins and various partners. Recent crystal structure analyses revealed essential self-interacting domains, while liquid-liquid phase separation contributes to their formation. PML bodies orchestrate post-translational modifications, particularly stress-induced SUMOylation, impacting target protein functions. Serving as hubs in multiple signaling pathways, they influence cellular processes like senescence. Dysregulation of PML expression contributes to diseases, including cancer, highlighting their significance. Therapeutically, PML bodies are promising targets, exemplified by successful acute promyelocytic leukemia treatment with arsenic trioxide and retinoic acid restoring PML bodies. Understanding their functions illuminates both normal and pathological cellular physiology, guiding potential therapies. This review explores recent advancements in PML body biogenesis, biochemical activity, and their evolving biological roles.

Objective: Extramedullary relapse (EMR) is rare in acute promyelocytic leukemia (APL) and, there is a lack of information on its management. Current practices for EMR in APL are always to adopt strategies from other subtypes of Acute lymphoblastic leukemia (ALL) and Acute myeloid leukemia (AML). Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated a remarkable effect on EMR in FLT3-mutant AML. Therefore, it is worthwhile exploring if FLT3 mutation can be a therapeutic target and assessing the efficacy of Gilteritinib on FLT3-mutant EMR in APL., Methods: We described three cases of FLT3-mutant EMR in APL, comprising two isolated EMR cases and one systemic relapse. The patients underwent treatment with Gilteritinib-based regimens based on FLT3 mutation., Results: All three patients achieved complete regression of EMR, and no signs of tumor lysis syndrome during Gilteritinib-based therapy, only patient 1 showed mild granulocytopenia. They all maintained molecular complete remission (mCR) during the follow-up period., Conclusions: The Gilteritinib-based regimen shows a high and sustained therapeutic effect with minimal adverse effects, and provides a valuable experience for further evaluation in EMR APL patients.

Objective: To describe the prognostic variables and course of paediatric acute promyelocytic leukaemia (APL) in Pakistan., Study Design: Cohort study. Place and Duration of the Study: Department of Paediatric Oncology, Combined Military Hospital, Rawalpindi, Pakistan, from January 2012 to December 2022., Methodology: Patients aged 1-15 years, clinically confirmed APL with promyelocytic leukaemia- retinoic acid receptor alpha (PML-RARA) were enrolled. Initial admission included a thorough examination, recording demographic and clinical data, reporting time, prior treatment, and socioeconomic status. Statistical analysis used SPSS 25.0, with significance at p <0.05., Results: This study included 50 cases of APL. Out of which, 32 (64%) were males and 18 (34%) were females. The mean age at diagnosis was 7.02 ± 3.86 years. Pallor (96%) and fever (88%) were common presentations. The average white blood cell count was 28.70 ± 35.39 x109/L. Treatment protocols include 48% International Consortium for Childhood (ICC)-APL, and 52% arsenic trioxide (ATO). High-risk cases were 54%. Neutropenic fever and differentiation syndrome were common induction complications. Delays over one month increased induction deaths (6.7 to 35%, p = 0.011), reducing disease-free survival (DFS), (76.7 to 35%, p = 0.001), and overall survival (OS), (80 to 45%, p = 0.007). After 40.90 ± 45.19 months' follow-up, 10-year OS and DFS were 66.0% and 60.0%, respectively. The best OS and DFS, at 80%, were observed in standard-risk cases treated with ATO., Conclusion: Neutropenic fever and bleeding were the primary causes of mortality in paediatric APL induction. Treatment delay was a key prognostic factor. ATO-based therapy offered safer, improved DFS, and OS suitable for primary healthcare settings., Key Words: Acute promyelocytic leukaemia, Chemotherapy, Neutropenic fever.

The present study described an extremely rare case of acute promyelocytic leukemia (APL) characterized by a complex three‑way (15;22;17)(q22;q11.2;q21) translocation. Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia with distinctive clinical and therapeutic characteristics. Besides being characterized by the t(15;17)(q22;q12) translocation, this subtype is also notable for its response to all-trans-retinoic acid (ATRA) treatment. APL is highly responsive to a combination of ATRA and chemotherapeutic agents, achieving over 90 % complete remission rates and over 80 % long-term remission rates. In this case, a 79-year-old male patient presented with complaints of weakness, fatigue, and petechial rash, with no other significant medical history except for diabetes mellitus and hypertension. Conventional cytogenetic methods, dual-color dual-fusion, and dual-color break-apart fluorescent in situ hybridization techniques together identified the t(15;22;17) translocation. RT-PCR analysis was performed for expression of PML/RARA fusion transcripts. The patient, diagnosed with APL, exhibited a complete response to all-trans retinoic acid (ATRA) and idarubicin treatment. In this paper, we present the second documented case of t(15;22;17) and explore the remarkable remission observed following treatment with All-Trans Retinoic Acid (ATRA)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Arsenic trioxide (ATO) is expected to be a chemical drug with antitumor activity against acute promyelocytic leukemia (APL), a type of acute myeloid leukemia. In Japan, its antitumor effects were confirmed in clinical trials for APL, and it has been approved in various countries around the world. However, there have been no reports on ATO's antitumor effects on radioresistant leukemia cells, which can be developed during radiotherapy and in combination with therapeutic radiation beams. The present study sought to clarify the antitumor effect of ATO on APL cells with radiation resistance and determine its efficacy when combined with ionizing radiation (IR). The radiation‑resistant HL60 (Res‑HL60) cell line was generated by subjecting the native cells to 4‑Gy irradiation every week for 4 weeks. The half‑maximal inhibitory concentration (IC 50 ) for cell proliferation by ATO on native cell was 0.87 µM (R 2 =0.67), while the IC 50 for cell proliferation by ATO on Res‑HL60 was 2.24 µM (R 2 =0.91). IR exposure increased the sub‑G1 and G2/M phase ratios in both cell lines. The addition of ATO resulted in a higher population of G2/M after 24 h rather than 48 h. When the rate of change in the sub‑G1 phase was examined in greater detail, the sub‑G1 phase in both control cells without ATO significantly increased by exposure to IR at 24 h, but only under the condition of 2 Gy irradiation, it had continued to increase at 48 h. Res‑HL60 supplemented with ATO showed a higher rate of sub‑G1 change at 24 h; however, 2 Gy irradiation resulted in a decrease compared with the control. There was a significant increase in the ratio of the G2/M phase in cells after incubation with ATO for 24 h, and exposure to 2 Gy irradiation caused an even greater increase. To determine whether the inhibition of cell proliferation and cell cycle disruptions is related to reactive oxygen species (ROS) activity, intracellular ROS levels were measured with a flow cytometric assay. Although the ROS levels of Res‑HL60 were higher than those of native cells in the absence of irradiation, they did not change after 0.5 or 2 Gy irradiation. Furthermore, adding ATO to Res‑HL60 reduced intracellular ROS levels. These findings provide important information that radioresistant leukemia cells respond differently to the antitumor effect of ATO and the combined effect of IR.

There is an urgent need for an oral, efficient and safe regimen for high-risk APL under the pandemic of COVID-19. We retrospectively analysed 60 high-risk APL patients. For induction therapy (IT), in addition to all-trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650-1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8-44) versus 35 days (32-42; p = 0.75) and 3 months (0.8-3.5) versus 3.3 months (2.4-3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2-year estimated overall survival and event-free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Despite successful treatment regimens and remission rates of greater than 90%, early death is a concern for patients with acute promyelocytic leukemia (APL). The challenges surrounding proper care for APL are centered on the low volume of patients, which limits healthcare professionals' knowledge of disease management., Objectives: The purpose of this project was to develop resources and present an educational module specific to managing patients newly diagnosed with APL. An intervention to evaluate bedside nurses' knowledge of APL was implemented., Methods: Thirty-four RNs were recruited for participation. A clinical practice guideline, an algorithm, and a fact sheet were developed to provide resources for providers. An educational module was presented to the RNs to increase their knowledge of APL. Pre- and postintervention surveys were created to assess knowledge and confidence before and after the intervention., Findings: Thirty-four RNs completed the module, and 27 participated in the pre- and postintervention surveys. Mean knowledge test scores increased significantly from 7.19 preintervention to 14.04 postintervention (p < 0.001).

Cancer stem cells (CSCs) drive malignant tumor progression, recurrence, and metastasis with unique characteristics, including self-renewal and resistance to conventional treatments. Conventional differentiation inducers, although promising, have limited cytotoxicity and may inadvertently enhance CSC stemness. To address these challenges, ongoing efforts are dedicated to developing strategies that can effectively combine both cytotoxicity and differentiation-inducing effects. In this study, we introduce oridonin (Ori), a small molecule with dual differentiation-inducing and cytotoxicity properties capable of eliminating tumor CSCs. We isolated CSCs in B16F10 cells using the Hoechst side population method and assessed the differentiation effect of Ori. Ori's differentiation-inducing effect was further evaluated using human acute promyelocytic leukemia. The cytotoxic potential of Ori against MCF-7 and B16F10 cell lines was assessed through various methods. In vivo anti-tumor and anti-CSC efficacy of Ori was investigated using mouse melanoma and CSCs melanoma models. Safety evaluation included zebrafish embryotoxicity and mouse acute toxicity experiments. As a result, Ori effectively dismantles tumorspheres, inhibits proliferation, and reduces the expression of CSC-specific markers. It induces significant differentiation, especially in the case of NB4. Additionally, Ori upregulates TP53 expression, mitigates the hypoxic tumor microenvironment, suppresses stemness, and inhibits PD-L1 expression, prompting a robust anti-cancer immune response. Ori demonstrates pronounced cytotoxicity, inducing notable pro-apoptotic effects on B16F10 and MCF-7 cells, with specific triggering of mitochondrial apoptosis. Importantly, Ori maintains a commendable biosafety record. The dual-action prowess of Ori not only induces the differentiation of CSCs but also dispatches differentiated and residual tumor cells, effectively thwarting the relentless march of tumor progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In the present study, the apoptosis-inducing potential of a chloroform fraction from an alcoholic extract of Vallaris solanacea aerial parts (VS) was examined using human promyelocytic leukemia HL-60 cells. We discovered a concentration and time-dependent decrease in cell growth using MTT assay. Scanning electron micrographs and fluorescence microscopy were used to observe several well-documented morphological and nuclear alterations, such as reduction in cell size, chromatin condensation, fragmentation, and the creation of cell surface blebs. A considerable rise in the Sub-G 0 population was revealed by cell cycle analysis. Additionally, a dose-dependent rise in cells positive for Annexin V was observed. DCFH-DA test on VS-treated HL-60 cells showed an increase in endogenous ROS generation of up to 4.3 fold. Additionally, suppression in Bcl-2 levels and increased mitochondrial membrane depolarization in treated cells were also associated with a rise in cytosolic cytochrome-c levels that was consequently followed by the activation of the caspase cascade. Further, the DNA fragmentation assay exhibited a typical ladder formation at 25 μg/ml, which became prominent in a concentration-dependent manner. Our study revealed that VS has apoptosis-inducing potential towards HL-60 cells in vitro and is an effective candidate for further anti-cancer studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Cell-free DNA (cfDNA) is free DNA found in circulating blood that originates from apoptosis or necrosis, and elevated cfDNA concentrations have been reported in cancers and other diseases., Methods: In this study, the concentrations and fragment distributions of plasma cfDNA were preliminary investigated in elderly ( n = 1) and paediatric ( n = 1) patients with acute promyelocytic leukaemia (APL) treated with arsenic trioxide (ATO)., Results: A slight increase in cfDNA concentrations was observed in the APL patients compared with healthy controls. The change in plasma cfDNA concentrations corresponded to the change in plasma arsenic concentrations during ATO treatment. The fragment distribution pattern did not differ before and during treatment. Three ladder fragments were observed in part of the cfDNA in the second consolidation therapy in an elderly APL patient and the first consolidation therapy of a paediatric APL patient, while two fragments were observed in all other treatment periods. Moreover, APL-related gene mutations were successfully genotyped from plasma cfDNA by using polymerase chain reaction-based methods and these results are consistent with those from leukocytes., Conclusion: This study is the first to report the concentrations and fragment patterns of cfDNA from APL patients treated with ATO. The results suggested that plasma cfDNA concentration in APL patients increased with ATO treatment and that cfDNA is released mainly via neutrophil extracellular traps (and/or necrosis) in addition to apoptosis. To confirm whether cfDNA concentrations and fragment patterns can be used as a biomarker for APL treated with ATO, further accumulative data are needed., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90-100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA., (© 2024. The Author(s).)

All- trans retinoic acid (ATRA), the major active metabolite of all- trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.

Background: The outcome of patients with acute promyelocytic leukemia (APL) has improved significantly since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as APL therapies. The optimal therapy for APL relapse is believed to require autologous or allogeneic stem cell transplantation (SCT) based on historical experience., Study Aims: To evaluate the outcome of patients with relapsed APL before and after the era of ATRA-ATO., Patients and Methods: We reviewed 61 patients with relapsed APL treated from November 1991 to June 2023; 31 patients (51%) received modern therapy with the combination of ATRA and ATO with and without idarubicin and gemtuzumab ozogamicin (GO)., Results: Overall, 56 patients (92%) achieved CR after the first salvage therapy; 20 patients received SCT (10 autologous SCT;10 allogeneic SCT). With a median follow-up time of 138 months, the median survival durations were 32 months and 164 months with historical therapy vs. modern (ATRA-ATO) therapy (P = .035); the 5-year survival rates were 44% vs. 71%. With a 10-month landmark analysis, the median survival durations were 102 months vs. not reached, and the 5-year survival rates were 57% and 70% without SCT vs. with SCT (P = .193). The survival benefit with SCT was more prominent in the historical therapy era. However, patients who received the modern combination therapy of ATRA-ATO with and without idarubicin and GO had similar outcomes without vs. with SCT (P = .848)., Conclusion: The combination of ATRA-ATO (+/- GO and idarubicin) is a highly effective salvage therapy in relapsed APL. The use of SCT may not be needed after first relapse-second remission but may be considered in subsequent relapses., Competing Interests: Disclosure Koji Sasaki reports personal fees from Otsuka and Pfizer, outside the submitted work; research funding from Novartis; advisory boards from Novartis. Farhad Ravandi reports research funding from Amgen, Cyclacel LTD, Macrogenix, Menarini Ricerche, Selvita, and Xencor; and personal fees from Amgen, Macrogenix, and Xencor, all outside the submitted work. Guillermo Garcia-Manero reports grants or research support from Amphivena, Helsinn, Novartis, AbbVie, Bristol-Myers Squibb, Astex, Onconova, H3 Biomedicine, Merck, Curis, Janssen, Genentech, Forty Seven, and Aprea; and personal fees from Bristol-Myers Squibb, Astex, Helsinn, and Genentech outside the submitted work. Tapan Kadia reports research Funding from AbbVie, Amgen, BioLine Rx, Bristol‐Myers Squibb, Celgene, Jazz, and Pfizer; and personal fees from AbbVie, Amgen, Genentech, Jazz, Pfizer, Pharmacyclics, and Takeda, all outside the submitted work. Courtney DiNardo reports personal fees and honoraria from AbbVie, Agios, Celgene, Daiichi Sankyo, Jazz, Medimmune, and Syros, all outside the submitted work. Musa Yilmaz reports research funding from Pfizer and Daiichi-Sankyo. Nicholas Short reports research funding from Takeda Oncology; and personal fees from Amgen, AstraZeneca, and Takeda Oncology, all outside the submitted work. Gautam Borthakur reports research funding from AbbVie, Agensys, Arvinas, AstraZeneca, Bayer Healthcare AG, BioLine Rx, Bristol‐Myers Squibb, Cantargia AB, Cyclacel, Eli Lilly and Company, Esai, GlaxoSmithKline, Incyte, Merck, Novartix, Oncoceutics, Polaris, Tetralogic Pharmaceuticals, and XBiotech USA; and personal fees from Argenx, BioLine Rx, BioTheryX, FTC Therapeutics, NKarta, Strategia Therapeutics, and TPC Therapeutics, all outside the submitted work. Hagop Kantarjian reports research grants and honoraria from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis, Pfizer and Sanofi; honoraria from Actinium (Advisory Board), Adaptive Biotechnologies, Aptitude Health, BioAscend, Delta Fly, Janssen Global, Oxford Biomedical and Takeda Oncology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Arsenicals have a special place in the history of human health, acting both as poison and medicine. Having been used to treat a variety of diseases in the past, the success of arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL) in the last century marked its use as a drug in modern medicine. To expand their role against cancer, there have been clinical uses of arsenicals worldwide and progress in the development of drug delivery for various malignancies, especially solid tumors., Areas Covered: In this review, conducted on Google Scholar [1977-2024], we start with various forms of arsenicals, highlighting the well-known ATO. The mechanism of action of arsenicals in cancer therapy is then overviewed. A summary of the research progress in developing new delivery approaches (e.g. polymers, inorganic frameworks, and biomacromolecules) in recent years is provided, addressing the challenges and opportunities in treating various malignant tumors., Expert Opinion: Reducing toxicity and enhancing therapeutic efficacy are guidelines for designing and developing new arsenicals and drug delivery systems. They have shown potential in the fight against cancer and emerging pathogens. New technologies and strategies can help us harness the potency of arsenicals and make better products.

Objectives: Outcomes of childhood acute promyelocytic leukemia (APL) have exceeded 90% in the era of differentiating agents. In resource-limited settings, early mortality secondary to coagulopathy remains a significant challenge. Differentiation syndrome is a unique complication of APL therapy that requires a high degree of suspicion for timely initiation of therapy., Methods: A retrospective study of children ≤15 y of age with APL diagnosed between January-2013 and June-2019 treated at a tertiary cancer centre was conducted. Patients with a total leukocyte count ≥10,000/µL were risk stratified as high-risk. Treatment included differentiating agents, all-trans retinoic acid and arsenic trioxide along with chemotherapy. Baseline demographics, clinical complications and outcomes were analysed., Results: Out of 90 patients treated, 48 (53%) had high-risk APL and 25 (28%) presented with significant bleeding manifestations. Response to therapy was excellent with 96% of evaluable patients achieving molecular remission by the end of consolidation phase. Differentiation syndrome occurred in 23 (25%) patients of which two expired. Early mortality rate was 5.5% and was due to severe hemorrhage most often at the time of presentation. The 3-y overall survival of the entire cohort was 91% (95% CI: 85-97%). Two of 4 patients with relapse of disease could be salvaged with only differentiating agents followed by autologous transplantation., Conclusions: Long-term outcomes of Indian children with APL are excellent. Timely management of coagulopathy and prompt initiation of differentiating agents along with appropriate cytoreductive measures is critical. Efforts to build academic-community partnerships to ensure timely diagnosis and emergency care in order to reduce early mortality are needed., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Despite therapeutic advances for acute promyelocytic leukemia (APL) with the emergence of all-trans retinoic acid, arsenic trioxide, and gemtuzumab-ozogamycin, approximately 10% of patients still experience disease relapse, typically occurring within 24 to 36 months following completion of front-line treatment. Traditionally, both allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) have been considered reasonable treatment options for relapsed APL; however, no randomized controlled studies have been conducted comparing allo-HCT and auto-HCT in patients with relapsed APL. We performed a systematic review/meta-analysis to assess the totality of evidence pertaining to allo-HCT or auto-HCT in relapsed APL. Our search identified 1158 references, of which 23 met our inclusion criteria. While acknowledging the limitations of comparing these 2 treatment modalities indirectly, based on results from separate meta-analyses, it appears that pooled rates of event-free survival (71% versus 54%), progression-free survival (63% versus 43%), and overall survival (82% versus 58%) are higher after auto-HCT. This difference can be explained in part by the higher risk of pooled nonrelapse mortality (NRM) in patients undergoing allo-HCT (29% versus 5%), owing to inherent risks associated with this modality. In the absence of a randomized prospective clinical trial comparing allo-HCT and auto-HCT, our results show that both modalities are acceptable in patients with relapsed APL. The higher pooled NRM rate with allo-HCT is an important consideration when choosing this option. Additionally, the comparable pooled relapse rate for auto-HCT and allo-HCT (24% versus 23%) provides a rationale for evaluating post-HCT consolidative strategies to mitigate this risk., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

For acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) is well established. However, the narrow application and tolerance development of ATRA remain to be improved. In this study, we investigated the effects of combinations of glycosylation inhibitors with ATRA to achieve better efficiency than ATRA alone. We found that the combination of fucosylation inhibitor 6-alkynylfucose (6AF) and ATRA had an additional effect on cell differentiation, as revealed by expression changes in two differentiation markers, CD11b and CD11c, and significant morphological changes in NB4 APL and HL-60 acute myeloid leukemia (AML) cells. In AAL lectin blot analyses, ATRA or 6AF alone could decrease fucosylation, while their combination decreased fucosylation more efficiently. To clarify the molecular mechanism for the 6AF effect on ATRA-induced differentiation, we performed microarray analyses using NB4 cells. In a pathway analysis using DAVID software, we found that the C-type lectin receptor (CLR) signaling pathway was enriched with high significance. In real-time PCR analyses using NB4 and HL-60 cells, FcεRIγ, CLEC6A, CLEC7A, CASP1, IL-1β, and EGR3, as components of the CLR pathway, as well as CD45 and AKT3 were upregulated by 6AF in ATRA-induced differentiation. Taken together, the present findings suggest that the CLR signaling pathway is involved in the 6AF effect on ATRA-induced differentiation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: All-trans retinoic acid (ATRA) is an indispensable part of the treatment of acute promyelocytic leukemia (APL). Although, mild cutaneous toxicities like mucocutaneous xerosis, rash, and pruritus are well reported, ATRA associated severe dermatological toxicities are extremely rare. ATRA is primary metabolized by cytochrome P450 (CYP450) enzyme system, and triazole antifungals are notorious for their strong inhibitory effect on CYP450., Case Presentation: Three Asian APL patients experienced rare ATRA-induced severe dermatological toxicities: exfoliative dermatitis (ED) in cases 1 and 2, and necrotic scrotal ulceration in case 3. Both case 1 (33-year-old female), and case 2 (28-year-old male) landed in emergency department with dehydration, generalized skin erythema and xerosis during their induction chemotherapy. Both of these patients also developed invasive aspergillosis and required concomitant triazole antifungals during their chemotherapy. For ED, intravenous fluids and broad-spectrum antibiotics were started along with application of local emollients to prevent transdermal water loss. Although their general condition improved but skin exfoliation continued with complete desquamation of palms and soles. Dermatology was consulted, and clinical diagnosis of ED was established. Discontinuation of ATRA resulted in complete resolution of ED. Case 3 (15-year-old boy) reported two blackish mildly tender scrotal lesions during induction chemotherapy. He also had mucocutaneous candidiasis at presentation and was kept on triazole antifungal. Local bacterial & fungal cultures, and serological testing for herpes simplex virus were reported negative. Despite adequate local care and optimal antibiotic support, his lesions persisted, and improved only after temporary discontinuation of ATRA. After a thorough literature review and considering the temporal association of cutaneous toxicities with triazole antifungals, we speculate that the concomitant use of triazole antifungals inhibited the hepatic metabolism of ATRA, resulting in higher serum ATRA concentration, and markedly accentuated cutaneous toxicities in our patients., Conclusion: By highlighting this crucial pharmacokinetic interaction, we want to caution the fellow oncologists to be mindful of the inhibitory effect of triazole antifungals on CYP450. We propose using a non-myelosuppressive combination of ATRA and arsenic trioxide for management of APL hence, obliterating the need of prophylactic antifungals. However, in the event of invasive fungal infection (IFI), we suggest using alternative class of antifungals., (© 2024. The Author(s).)

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-PML A216V -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 PML A216V -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 PML A216V -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 PML A216V -RARα., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Differentiation therapy using all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) is well established. However, because the narrow application and tolerance development of ATRA need to be improved, we searched for another efficient myeloid differentiation inducer. Kinase activation is involved in leukemia biology and differentiation block. To identify novel myeloid differentiation inducers, we used a Kinase Inhibitor Screening Library. Using a nitroblue tetrazolium dye reduction assay and real-time quantitative PCR using NB4 APL cells, we revealed that, PD169316, SB203580, SB202190 (p38 MAPK inhibitor), and triciribine (TCN) (Akt inhibitor) potently increased the expression of CD11b. We focused on TCN because it was reported to be well tolerated by patients with advanced hematological malignancies. Nuclear/cytoplasmic (N/C) ratio was significantly decreased, and myelomonocytic markers (CD11b and CD11c) were potently induced by TCN in both NB4 and acute myeloid leukemia (AML) M2 derived HL-60 cells. Western blot analysis using NB4 cells demonstrated that TCN promoted ERK1/2 phosphorylation, whereas p38 MAPK phosphorylation was not affected, suggesting that activation of the ERK pathway is involved in TCN-induced differentiation. We further examined that whether ATRA may affect phosphorylation of ERK and p38, and found that there was no obvious effect, suggesting that ATRA induced differentiation is different from TCN effect. To reveal the molecular mechanisms involved in TCN-induced differentiation, we performed microarray analysis. Pathway analysis using DAVID software indicated that "hematopoietic cell lineage" and "cytokine-cytokine receptor interaction" pathways were enriched with high significance. Real-time PCR analysis demonstrated that components of these pathways including IL1β, CD3D, IL5RA, ITGA6, CD44, ITGA2B, CD37, CD9, CSF2RA, and IL3RA, were upregulated by TCN-induced differentiation. Collectively, we identified TCN as a novel myeloid cell differentiation inducer, and trials of TCN for APL and non-APL leukemia are worthy of exploration in the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Suzuki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic-induced neurotoxicity is a well-recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic-based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any-grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1-2 severity (85%), with grade 3 events in 12% and grade 4-5 in 3%. The incidence of neurotoxicity increased with BMI (non-obese: 16%, obesity class I: 25%, obesity class II-III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II-III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II-III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre-emptive dose reductions should be considered for obese patients receiving high doses of arsenic., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

In order to explore the risk factors of relapse and potential optimized therapeutic regimen of low-risk acute promyelocytic leukaemia (APL), here we retrospectively analysed 282 patients who were diagnosed between February 2014 and September 2021. The median follow-up was 59 (9-102) months. The 5-year overall survival and cumulative relapse incidence were 97.9% and 5.9%, respectively. In terms of different cytoreductive therapies, 86 patients were administered with hydroxycarbamide (30.5%), 113 with anthracyclines or cytarabine (40.1%), 31 with etoposide (11.0%) and 52 with no cytoreductive therapy (18.4%) during the induction therapy. The hydroxycarbamide treatment group did not decrease the relapse rate compared to the no cytoreduction group (11.4% vs. 5.9%, p = 0.289). Compared with the hydroxycarbamide group, the anthracyclines/cytarabine treatment group showed improved 5-year RFS (88.145% vs. 98.113%, p = 0.008). Multivariate Cox regression analysis revealed that myeloblasts in bone marrow at diagnosis, and PML-RARA transcript level of 6.5% or more after induction therapy were associated with a subsequent risk of relapse. The only factor positively reducing the relapse rate was anthracyclines/cytarabine cytoreductive treatment. In conclusion, cytoreductive chemotherapy in induction therapy plays a potential key role in the prognosis of low-risk APL., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Introduction: Early death (ED) is the unsolved issue of acute promyelocytic leukemia (APL). The disseminated intravascular coagulation (DIC) score has been proposed as a marker of bleeding and death in APL; whether its temporal evolution predicts outcomes in APL is unknown. We evaluated whether an increasing score 48 h after diagnosis associates with ED., Methods: Retrospective, single-center study, including patients with newly diagnosed APL between 2000 and 2023, treated with all-transretinoic acid (ATRA) plus anthracycline or arsenic trioxide (ATO). "DIC score worsening" was defined as ≥1 point increase in the score after 48 h, and ED as death within 30 days of diagnosis., Results: Eighty-six patients were included, with median age of 46 years (17-82). ED patients (26.7%) more frequently had age >60 years and worsening DIC score after 48 h. These were also the only predictors of ED identified in both univariate and multivariate (OR 4.18, p = .011; OR 7.8, p = .005, respectively) logistic regression analysis., Conclusion: This is the first study on DIC score evolution in APL-a worsening DIC score 48 h after diagnosis is a strong independent predictive factor of ED. We propose a reduction of the DIC score from diagnosis as a new treatment goal in APL care., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Acute promyelocytic leukemia (APL) is a highly curable hematologic malignancy in the era of all-trans retinoic acid (ATRA) combination treatment. However, only a modest change in early mortality rate has been observed despite the wide availability of ATRA. In addition to the clinical characteristics of APL patients, studies on the hospital volume-outcome relationship and the physician volume-outcome relationship remained limited. We aim to evaluate the association between hospital and physician volume and the early mortality rate among APL patients. The patients were collected from Taiwan's National Health Insurance Research Database (NHIRD). Early mortality is defined as death within 30 days of diagnosis. Patients were categorized into four groups according to individual cumulative hospital and physician volume. The risk of all-cause mortality in APL patients with different cumulative volume groups was compared using a Cox proportional hazard model. The probability of overall survival was estimated using the Kaplan-Meier method. All 741 patients were divided into four quartile volume groups. In the multivariate analysis, only physician volume was significantly associated with early mortality rate. The physician volume of the highest quartile was a protective factor for early mortality compared with the physician volume of the lowest quartile (HR 0.10, 95% CI 0.02-0.65). Hospital characteristics were not associated with early mortality. In the sensitivity analyses, the results remained consistent using two other different definitions of early mortality. Higher physician volume was independently associated with lower early mortality, while hospital volume was not. Enhancing the clinical expertise of low-volume physicians may ensure better outcomes., (© 2024. The Author(s).)

The success of arsenic in acute promyelocytic leukemia (APL) treatment is hardly transferred to non-APL cancers, mainly due to the low selectivity and weak binding affinity of traditional arsenicals to oncoproteins critical for cancer survival. We present herein the reinvention of aliphatic trivalent arsenicals (As) as reversible covalent warheads of As-based targeting inhibitors toward Bruton's tyrosine kinase (BTK). The effects of As warheads' valency, thiol protection, methylation, spacer length, and size on inhibitors' activity were studied. We found that, in contrast to the bulky and rigid aromatic As warhead, the flexible aliphatic As warheads were well compatible with the well-optimized guiding group to achieve nanomolar inhibition against BTK. The optimized As inhibitors effectively blocked the BTK-mediated oncogenic signaling pathway, leading to elevated antiproliferative activities toward lymphoma cells and xenograft tumor. Our study provides a promising strategy enabling rational design of new aliphatic arsenic-based reversible covalent inhibitors toward non-APL cancer treatment.

The treatment of PML/RARA+ acute promyelocytic leukemia (APL) with all-trans-retinoic acid and arsenic trioxide (ATRA/ATO) has been recognized as a model for translational medicine research. Though an altered microenvironment is a general cancer hallmark, how APL blasts shape their plasma composition is poorly understood. Here, we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters, proteomes, and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy. Our study revealed the two prominent features of the APL plasma, suggesting a possible involvement of APL blasts in modulating plasma composition. One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts, and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA. Furthermore, results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage, which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins. Overall, our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment., (© 2023. Higher Education Press.)

Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia that is distinguished by the chromosomal translocation t(15;17)(q24;q21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA). Recently, we identified a novel fusion gene in APL, RARA::ankyrin repeat domain 34C (ANKRD34C), identified its functions by morphological, cytogenetic, molecular biological and multiplex fluorescence in situ hybridization analyses, and demonstrated the potential therapeutic effect clinically and experimentally of all-trans retinoic acid (ATRA); the findings have important implications for the diagnosis and treatment of atypical APL., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)