{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T01:45:05Z","timestamp":1791942305880,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Institute de Recherche sur le Cancer","award":["Ref: 1820\/2025"],"award-info":[{"award-number":["Ref: 1820\/2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hematology Reports"],"abstract":"<jats:p>Background\/Objectives: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by the t(15;17)(q24;q21) translocation, generating the PML::RARA fusion gene that blocks myeloid differentiation and drives leukemogenesis. Despite advances in therapy, early mortality remains a major challenge due to severe coagulopathy. This review aims to summarize recent insights into APL pathophysiology, diagnostic approaches, and management strategies. Methods: We performed a comprehensive review of the literature addressing the molecular mechanisms of APL, its associated coagulopathy, and current diagnostic and therapeutic standards, with a focus on evidence-based recommendations for clinical practice. Results: The hallmark PML: RARA oncoprotein disrupts nuclear body function and retinoic acid signaling, resulting in differentiation arrest and apoptosis resistance. APL-associated coagulopathy arises from overexpression of tissue factor, release of cancer procoagulant, inflammatory cytokines, and annexin II-mediated hyperfibrinolysis. Diagnosis requires integration of cytomorphology, immunophenotyping, coagulation studies, and molecular confirmation. Immediate initiation of all-trans-retinoic acid (ATRA) upon clinical suspicion, combined with aggressive supportive care, is critical to control bleeding risk. Conclusions: APL is now a highly curable leukemia when recognized early and treated with targeted therapy. Rapid diagnosis, prompt ATRA administration, and meticulous hemostatic support are essential to reduce early mortality. Further refinements in minimal residual disease monitoring are expected to improve patient outcomes.<\/jats:p>","DOI":"10.3390\/hematolrep17060066","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T17:35:17Z","timestamp":1764956117000},"page":"66","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Acute Promyelocytic Leukemia: Pathophysiology, Diagnosis and Clinical Management"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8735-1429","authenticated-orcid":false,"given":"Meryeme","family":"Abddaoui","sequence":"first","affiliation":[{"name":"Laboratory of Medical Sciences and Translational Research, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, Sidi Mohammed Ben Abdellah University, F\u00e8s 30070, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3287-9542","authenticated-orcid":false,"given":"Youssef","family":"Aghlallou","sequence":"additional","affiliation":[{"name":"Institute of Cancer Research, F\u00e8s 30000, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imane","family":"Tlem\u00e7ani","sequence":"additional","affiliation":[{"name":"Department of Hematology, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, F\u00e8s 30070, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moncef","family":"Amrani Hassani","sequence":"additional","affiliation":[{"name":"Department of Hematology, Faculty of Medicine, Pharmacy and Dental Medicine of Fez, F\u00e8s 30070, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bidikian, A., Bewersdorf, J.P., Kewan, T., Stahl, M., and Zeidan, A.M. (2024). Acute Promyelocytic Leukemia in the Real World: Understanding Outcome Differences and How We Can Improve Them. Cancers, 16.","DOI":"10.3390\/cancers16234092"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3892\/ol.2024.14246","article-title":"Acute Promyelocytic Leukemia with PML\/RARA (Bcr1, Bcr2 and Bcr3) Transcripts in a Pediatric Patient","volume":"27","year":"2024","journal-title":"Oncol. Lett."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Eckardt, J.-N., Schmittmann, T., Riechert, S., Kramer, M., Sulaiman, A.S., Sockel, K., Kroschinsky, F., Schetelig, J., Wagenf\u00fchr, L., and Schuler, U. (2022). Deep Learning Identifies Acute Promyelocytic Leukemia in Bone Marrow Smears. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09307-8"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhang, X., Sun, J., Yu, W., and Jin, J. (2021). Current Views on the Genetic Landscape and Management of Variant Acute Promyelocytic Leukemia. Biomark. Res., 9.","DOI":"10.1186\/s40364-021-00284-x"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Iyer, S.G., Elias, L., Stanchina, M., and Watts, J. (2023). The Treatment of Acute Promyelocytic Leukemia in 2023: Paradigm, Advances, and Future Directions. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1062524"},{"key":"ref_6","first-page":"408","article-title":"H\u00e9morragie dans la leuc\u00e9mie aigu\u00eb promy\u00e9locytaire et au-del\u00e0: Les r\u00f4les du facteur tissulaire et des m\u00e9canismes de r\u00e9gulation sous-jacents","volume":"207","author":"Xi","year":"2023","journal-title":"Bull. Acad. Natl. M\u00e9d."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hermsen, J., and Hambley, B. (2023). The Coagulopathy of Acute Promyelocytic Leukemia: An Updated Review of Pathophysiology, Risk Stratification, and Clinical Management. Cancers, 15.","DOI":"10.3390\/cancers15133477"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1002\/ajh.23158","article-title":"Bleeding and Thrombosis in Acute Promyelocytic Leukemia","volume":"87","author":"Choudhry","year":"2012","journal-title":"Am. J. Hematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102499","DOI":"10.1016\/j.rpth.2024.102499","article-title":"Hemorrhage in Acute Promyelocytic Leukemia\u2014Fibrinolysis in Focus","volume":"8","author":"Sabljic","year":"2024","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1182\/hematology.2023000477","article-title":"How to Avoid Early Mortality in Acute Promyelocytic Leukemia","volume":"2023","author":"Odetola","year":"2023","journal-title":"Hematology"},{"key":"ref_11","first-page":"e70198","article-title":"Immunophenotypic Profiling of Acute Promyelocytic Leukemia: Insights From a Large Cohort","volume":"8","author":"Kankhaw","year":"2025","journal-title":"Cancer Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Klausner, M., Stinnett, V., Ghabrial, J., Morsberger, L., DeMetrick, N., Long, P., Zhu, J., Smith, K., James, T., and Adams, E. (2024). Optical Genome Mapping Reveals Complex and Cryptic Rearrangement Involving PML::RARA Fusion in Acute Promyelocytic Leukemia. Genes, 15.","DOI":"10.3390\/genes15111402"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1182\/blood-2017-07-794784","article-title":"Pml Nuclear Body Disruption Cooperates in APL Pathogenesis and Impairs DNA Damage Repair Pathways in Mice","volume":"131","author":"Voisset","year":"2018","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4278","DOI":"10.1158\/0008-5472.CAN-12-3814","article-title":"PML-RAR\u03b1 and Its Phosphorylation Regulate PML Oligomerization and HIPK2 Stability","volume":"73","author":"Shima","year":"2013","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/s41421-024-00735-3","article-title":"Cryo-EM Structure of PML RBCC Dimer Reveals CC-Mediated Octopus-like Nuclear Body Assembly Mechanism","volume":"10","author":"Tan","year":"2024","journal-title":"Cell Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"992","DOI":"10.18632\/oncotarget.27513","article-title":"Acute Promyelocytic Leukemia (APL): A Review of the Literature","volume":"11","author":"Jimenez","year":"2020","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"104822","DOI":"10.1016\/j.exphem.2025.104822","article-title":"Advances in RAR\u03b1 Fusion Genes in Acute Promyelocytic Leukemia","volume":"149","author":"Zhang","year":"2025","journal-title":"Exp. Hematol."},{"key":"ref_18","unstructured":"Chaudhry, R., Killeen, R.B., and Babiker, H.M. (2025). Physiology, Coagulation Pathways. StatPearls, StatPearls Publishing."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s44313-024-00040-8","article-title":"Back to Basics: The Coagulation Pathway","volume":"59","author":"Park","year":"2024","journal-title":"Blood Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Liquori, A., Iba\u00f1ez, M., Sargas, C., Sanz, M.\u00c1., Barrag\u00e1n, E., and Cervera, J. (2020). Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene. Cancers, 12.","DOI":"10.3390\/cancers12030624"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1007\/s00277-021-04533-9","article-title":"Tissue Factor\u2013Bearing Microparticles Are a Link between Acute Promyelocytic Leukemia Cells and Coagulation Activation: A Human Subject Study","volume":"100","author":"Zhao","year":"2021","journal-title":"Ann. Hematol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hambley, B.C., Tomuleasa, C., and Ghiaur, G. (2021). Coagulopathy in Acute Promyelocytic Leukemia: Can We Go Beyond Supportive Care?. Front. Med., 8.","DOI":"10.3389\/fmed.2021.722614"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"A903","DOI":"10.1016\/j.chest.2020.08.839","article-title":"A Different Killer: Early Death in Acute Promyelocytic Leukemia Presenting with Septic Shock","volume":"158","author":"Taylor","year":"2020","journal-title":"CHEST"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1182\/blood.2022015850","article-title":"International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: Integrating Morphologic, Clinical, and Genomic Data","volume":"140","author":"Arber","year":"2022","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Salman, H. (2024). Comparative Analysis of AML Classification Systems: Evaluating the WHO, ICC, and ELN Frameworks and Their Distinctions. Cancers, 16.","DOI":"10.3390\/cancers16162915"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/ejh.13872","article-title":"Auer Rods and Faggot Cells: A Review of the History, Significance and Mimics of Two Morphological Curiosities of Enduring Relevance","volume":"110","author":"Sehgal","year":"2023","journal-title":"Eur. J. Haematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"300753","DOI":"10.1016\/j.hpr.2024.300753","article-title":"Acute Promyelocytic Leukemia: A Rare Presentation without Systemic Disease","volume":"37","author":"Ladak","year":"2024","journal-title":"Hum. Pathol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.3324\/haematol.2022.280406","article-title":"Diagnosis of Acute Promyelocytic Leukemia Based on Routine Biological Parameters Using Machine Learning","volume":"107","author":"Cheli","year":"2022","journal-title":"Haematologica"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"119945","DOI":"10.1016\/j.cca.2024.119945","article-title":"Flow Cytometry in Acute Myeloid Leukemia and Detection of Minimal Residual Disease","volume":"564","author":"Cai","year":"2025","journal-title":"Clin. Chim. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1002\/cyto.b.22085","article-title":"Acute Promyelocytic Leukemia: Immunophenotype and Differential Diagnosis by Flow Cytometry","volume":"102","author":"Fang","year":"2022","journal-title":"Cytom. Part B Clin. Cytom."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"262","DOI":"10.5858\/arpa.2023-0460-OA","article-title":"Measurable Residual Disease Analysis by Flow Cytometry and Correlation With Molecular Measurable Residual Disease in Acute Promyelocytic Leukemia: A Real-World Prospective Study","volume":"149","author":"Wen","year":"2025","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1111\/ijlh.12636","article-title":"A Study of Disseminated Intravascular Coagulation in Acute Leukemia Reveals Markedly Elevated D-Dimer Levels Are a Sensitive Indicator of Acute Promyelocytic Leukemia","volume":"39","author":"Shahmarvand","year":"2017","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.htct.2024.05.002","article-title":"Diagnosis and Management of Acute Promyelocytic Leukemia: Brazilian Consensus Guidelines 2024 on Behalf of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy","volume":"46","author":"Catto","year":"2024","journal-title":"Hematol. Transfus. Cell Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1182\/blood-2019-01-894980","article-title":"Management of Acute Promyelocytic Leukemia: Updated Recommendations from an Expert Panel of the European LeukemiaNet","volume":"133","author":"Sanz","year":"2019","journal-title":"Blood"},{"key":"ref_35","first-page":"46","article-title":"Acute Myeloid Leukemia Management and Research in 2025","volume":"75","author":"Kantarjian","year":"2025","journal-title":"CA A Cancer J. Clin."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41698-025-01072-8","article-title":"Detection of Cytogenetically Cryptic PML-RARA Fusion in Acute Promyelocytic Leukemia by Rapid next Generation Sequencing","volume":"9","author":"Protopsaltis","year":"2025","journal-title":"NPJ Precis. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"103348","DOI":"10.1016\/j.eclinm.2025.103348","article-title":"Measurable Residual Disease in Hematologic Malignancies: A Biomarker in Search of a Standard","volume":"86","author":"Chandhok","year":"2025","journal-title":"eClinicalMedicine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and Management of AML in Adults: 2022 Recommendations from an International Expert Panel on Behalf of the ELN","volume":"140","author":"Wei","year":"2022","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"621566","DOI":"10.3389\/fonc.2021.621566","article-title":"Evolving Chemotherapy Free Regimens for Acute Promyelocytic Leukemia","volume":"11","author":"Kulkarni","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Woods, A.C., and Norsworthy, K.J. (2023). Differentiation Syndrome in Acute Leukemia: APL and Beyond. Cancers, 15.","DOI":"10.3390\/cancers15194767"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1111\/bjh.19759","article-title":"Leucocytosis during Induction Therapy with All-Trans-Retinoic Acid and Arsenic Trioxide in Acute Promyelocytic Leukaemia Predicts Differentiation Syndrome and Treatment-Related Complications","volume":"205","author":"Cicconi","year":"2024","journal-title":"Br. J. Haematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.1200\/JCO-25-00535","article-title":"Arsenic Trioxide and All-Trans Retinoic Acid Combination Therapy for the Treatment of High-Risk Acute Promyelocytic Leukemia: Results From the APOLLO Trial","volume":"43","author":"Platzbecker","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1182\/blood.2024026186","article-title":"Acute Promyelocytic Leukemia: Long-Term Outcomes from the HARMONY Project","volume":"145","author":"Voso","year":"2025","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1097\/CCO.0000000000001171","article-title":"Curative Strategies for High-Risk Acute Promyelocytic Leukemia","volume":"37","author":"Chin","year":"2025","journal-title":"Curr. Opin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/s41408-021-00514-3","article-title":"Acute Promyelocytic Leukemia Current Treatment Algorithms","volume":"11","author":"Yilmaz","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1182\/blood-2023-184433","article-title":"Recommendations on Minimal Residual Disease Monitoring in Acute Promyelocytic Leukemia Treated with Combination of All- Trans Retinoic Acid and Arsenic Trioxide","volume":"142","author":"Chen","year":"2023","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.clml.2024.01.015","article-title":"Outcome of Patients with Relapsed Acute Promyelocytic Leukemia","volume":"24","author":"Sasaki","year":"2024","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"599.e1","DOI":"10.1016\/j.jtct.2024.03.024","article-title":"Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Promyelocytic Leukemia: Results of a Systematic Review and Meta-Analysis","volume":"30","author":"Mohty","year":"2024","journal-title":"Transplant. Cell. Ther."}],"container-title":["Hematology Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2038-8330\/17\/6\/66\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T18:22:33Z","timestamp":1764958953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2038-8330\/17\/6\/66"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":48,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["hematolrep17060066"],"URL":"https:\/\/doi.org\/10.3390\/hematolrep17060066","relation":{},"ISSN":["2038-8330"],"issn-type":[{"value":"2038-8330","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]}}}