{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:49:14Z","timestamp":1789447754383,"version":"build-2803163510"},"reference-count":98,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Mixed-phenotype acute leukemia (MPAL) is a rare and heterogeneous subtype of acute leukemia, associated with unfavorable outcomes. MPAL is defined by the presence of more than 20% blasts and bi- or trilineage assignment based on strong immunophenotypic markers, with specific subcategories characterized by\n                      <jats:italic>BCR::ABL1<\/jats:italic>\n                      ,\n                      <jats:italic>KMT2A<\/jats:italic>\n                      ,\n                      <jats:italic>ZNF384<\/jats:italic>\n                      , or\n                      <jats:italic>BCL11B<\/jats:italic>\n                      rearrangements. This review aims to summarize current knowledge and challenges in the diagnosis and management of MPAL.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Data were synthesized primarily from meta-analyses and original studies, with a particular emphasis on the roles of immunophenotyping, cytogenetics, and novel targeted therapies from 1985 to the present.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MPAL accounts for 1%\u20135% of acute leukemias, with B\/myeloid (59%) and T\/myeloid (35%) subtypes being the most prevalent. Cytogenetic abnormalities are identified in up to 90% of cases, predominantly complex karyotypes. Molecular investigations have identified frequent mutations in genes such as\n                      <jats:italic>RUNX1<\/jats:italic>\n                      ,\n                      <jats:italic>DNMT3A<\/jats:italic>\n                      ,\n                      <jats:italic>IDH1\/2<\/jats:italic>\n                      ,\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      , and\n                      <jats:italic>FLT3<\/jats:italic>\n                      , particularly enriched in T\/myeloid MPAL. Adverse prognostic factors include\n                      <jats:italic>KMT2Ar<\/jats:italic>\n                      , elevated leukocyte counts, extramedullary disease, and bilineage disease biology. Generally, the prognosis for adults is poorer than for the pediatric population. No standardized treatment strategy has been established. Retrospective analyses indicate superior complete remission rates and overall survival with ALL-based regimens, and allogeneic hematopoietic stem cell transplantation remains crucial for improving survival. Recently, hybrid regimens such as FLAG-IDA and CLAG-M have demonstrated promising efficacy with acceptable toxicity. Targeted therapies are emerging options, although lineage switch under selective therapeutic pressure remains a concern.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>MPAL remains a significant challenge in diagnosis and treatment. Advances in molecular characterization have enhanced classification techniques and have the potential to inform personalized treatment strategies. Considering the rarity and heterogeneity of MPAL, extensive prospective multicenter trials are imperative to develop evidence-based therapeutic protocols.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fped.2025.1715087","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T06:28:11Z","timestamp":1765866491000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Mixed phenotype acute leukemia, the dissection of an enigmatic disease in the era of novel therapies"],"prefix":"10.3389","volume":"13","author":[{"given":"Magdalena","family":"Karasek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela","family":"Kubiszewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Sobas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th edition of the world health organization classification of haematolymphoid tumours: myeloid and histiocytic\/dendritic neoplasms","volume":"36","author":"Khoury","year":"2022","journal-title":"Leukemia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1182\/blood-2014-10-551465","article-title":"How I treat mixed-phenotype acute leukemia","volume":"125","author":"Wolach","year":"2015","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3163","DOI":"10.1182\/blood-2010-10-314682","article-title":"Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification","volume":"117","author":"Matutes","year":"2011","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.3324\/haematol.2012.064485","article-title":"Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification","volume":"97","author":"Yan","year":"2012","journal-title":"Haematologica"},{"key":"B5","doi-asserted-by":"publisher","first-page":"919","DOI":"10.3324\/haematol.2008.003202","article-title":"Clinical and biological characteristics of adult biphenotypic acute leukemia in comparison with that of acute myeloid leukemia and acute lymphoblastic leukemia: a case series of a Chinese population","volume":"94","author":"Xu","year":"2009","journal-title":"Haematologica"},{"key":"B6","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1111\/j.1365-2141.2009.08058.x","article-title":"Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations","volume":"149","author":"Gerr","year":"2010","journal-title":"Br J Haematol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1682","DOI":"10.3324\/haematol.2009.009282","article-title":"Clinical characteristics and outcome of children with biphenotypic acute leukemia","volume":"94","author":"Al-Seraihy","year":"2009","journal-title":"Haematologica"},{"key":"B8","first-page":"699","article-title":"Outcome of biphenotypic acute leukemia","volume":"84","author":"Killick","year":"1999","journal-title":"Haematologica"},{"key":"B9","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1016\/j.leukres.2015.03.012","article-title":"Survival of patients with mixed phenotype acute leukemias: a large population-based study","volume":"39","author":"Shi","year":"2015","journal-title":"Leuk Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1038\/s41375-018-0058-4","article-title":"Therapy for children and adults with mixed phenotype acute leukemia: a systematic review and meta-analysis","volume":"32","author":"Maruffi","year":"2018","journal-title":"Leukemia"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2134","DOI":"10.3324\/haematol.2017.174441","article-title":"Mixed phenotype acute leukemia: outcomes with allogeneic stem cell transplantation. 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