{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:24:00Z","timestamp":1791829440435,"version":"4.3.4"},"reference-count":52,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,12,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Despite the maximum intensification of chemotherapy and the increased use of hematopoietic stem cell transplantation (HCT) in pediatric patients with acute myeloid leukemia (AML), nearly 40% of patients still experience relapse, and cure in this setting remains a significant challenge. Recent improvements in AML characterization, including advances in flow cytometry and comprehensive genomic sequencing, have led to a better understanding of AML biology and the identification of multiple potential therapeutic targets. Novel agents targeting genomic lesions, cell surface antigens, and other mechanisms that permit oncogenesis or immune escape are being incorporated into current treatment strategies or are under investigation in efforts to improve outcomes and decrease the toxicities and late effects associated with traditional intensive chemotherapeutic and HCT treatment. However, multiple challenges still exist, including the biologic and immunophenotypic heterogeneity of childhood AML, the differences in underlying biology as compared to adult AML, and the significant potential for on-target\/off-tumor toxicity associated with therapies directed at targets common to myeloid cells, both leukemic and normal. This article reviews the current landscape of genomic and cell surface targets for children with AML with a focus on the currently available targeted therapeutic agents, those in active clinical investigation, and those still in development.<\/jats:p>","DOI":"10.1182\/hematology.2022000358","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T16:13:54Z","timestamp":1670602434000},"page":"603-610","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":18,"title":["The evolution of targeted therapy in pediatric AML: gemtuzumab ozogamicin, FLT3\/IDH\/BCL2 inhibitors, and other therapies"],"prefix":"10.1182","volume":"2022","author":[{"given":"Lauren","family":"Pommert","sequence":"first","affiliation":[{"name":"1 Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH"},{"name":"2 Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Tarlock","sequence":"additional","affiliation":[{"name":"3 Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, WA"},{"name":"4 Department of Pediatrics, University of Washington School of Medicine, Seattle, WA"},{"name":"5 Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"issue":"10","key":"2022121313282290200_hem2022000358C1","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.3390\/cancers13102336","article-title":"Survival following relapse in children with acute myeloid leukemia: a report from AML-BFM and COG","volume":"13","author":"Rasche","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"1","key":"2022121313282290200_hem2022000358C2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/MOP.0000000000000855","article-title":"Pediatric acute myeloid leukemia: updates on biology, risk stratification, and therapy","volume":"32","author":"Elgarten","year":"2020","journal-title":"Curr Opin Pediatr"},{"issue":"7","key":"2022121313282290200_hem2022000358C3","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.3324\/haematol.2019.220962","article-title":"Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group","volume":"105","author":"Aplenc","year":"2020","journal-title":"Haematologica"},{"issue":"27","key":"2022121313282290200_hem2022000358C4","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1200\/JCO.2014.55.3628","article-title":"Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children's Oncology Group trial AAML0531","volume":"32","author":"Gamis","year":"2014","journal-title":"J Clin Oncol"},{"issue":"1","key":"2022121313282290200_hem2022000358C5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nm.4439","article-title":"The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions","volume":"24","author":"Bolouri","year":"2018","journal-title":"Nat Med"},{"issue":"22","key":"2022121313282290200_hem2022000358C6","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","author":"Ley","year":"2013","journal-title":"N Engl J Med"},{"issue":"3","key":"2022121313282290200_hem2022000358C7","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1158\/2643-3230.BCD-21-0160","article-title":"Integrated genomic analysis identifies UBTF tandem duplications as a recurrent lesion in pediatric acute myeloid leukemia","volume":"3","author":"Umeda","year":"2022","journal-title":"Blood Cancer Discov"},{"issue":"41","key":"2022121313282290200_hem2022000358C8","doi-asserted-by":"crossref","first-page":"26417","DOI":"10.18632\/oncotarget.25443","article-title":"Distinct age-associated molecular profiles in acute myeloid leukemia defined by comprehensive clinical genomic profiling","volume":"9","author":"Tarlock","year":"2018","journal-title":"Oncotarget"},{"issue":"13","key":"2022121313282290200_hem2022000358C9","doi-asserted-by":"crossref","first-page":"4263","DOI":"10.1158\/1078-0432.CCR-08-1123","article-title":"Structural and functional alterations of FLT3 in acute myeloid leukemia","volume":"15","author":"Meshinchi","year":"2009","journal-title":"Clin Cancer Res"},{"issue":"12","key":"2022121313282290200_hem2022000358C10","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.1182\/blood-2006-03-009233","article-title":"Clinical implications of FLT3 mutations in pediatric AML","volume":"108","author":"Meshinchi","year":"2006","journal-title":"Blood"},{"issue":"23","key":"2022121313282290200_hem2022000358C11","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1182\/blood-2014-05-578070","article-title":"Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation","volume":"124","author":"Schlenk","year":"2014","journal-title":"Blood"},{"issue":"12","key":"2022121313282290200_hem2022000358C12","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.1038\/leu.2015.165","article-title":"FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors","volume":"29","author":"Smith","year":"2015","journal-title":"Leukemia"},{"issue":"5","key":"2022121313282290200_hem2022000358C13","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1056\/NEJMoa1614359","article-title":"Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation","volume":"377","author":"Stone","year":"2017","journal-title":"N Engl J Med"},{"issue":"9","key":"2022121313282290200_hem2022000358C14","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1038\/s41375-021-01179-4","article-title":"Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603\/RATIFY trial","volume":"35","author":"Larson","year":"2021","journal-title":"Leukemia"},{"issue":"18","key":"2022121313282290200_hem2022000358C15","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1200\/JCO.21.01612","article-title":"Sorafenib in combination with standard chemotherapy for children with high allelic ratio FLT3\/ITD+ acute myeloid leukemia: a report from the Children's Oncology Group protocol AAML1031","volume":"40","author":"Pollard","year":"2022","journal-title":"J Clin Oncol"},{"issue":"6","key":"2022121313282290200_hem2022000358C16","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1002\/pbc.25437","article-title":"Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3\/ITD acute myeloid leukemia","volume":"62","author":"Tarlock","year":"2015","journal-title":"Pediatr Blood Cancer"},{"issue":"2","key":"2022121313282290200_hem2022000358C17","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.bbmt.2019.09.023","article-title":"A prospective study of peritransplant sorafenib for patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic transplantation","volume":"26","author":"Pratz","year":"2020","journal-title":"Biol Blood Marrow Transplant"},{"issue":"26","key":"2022121313282290200_hem2022000358C18","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1200\/JCO.19.03345","article-title":"Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN)","volume":"38","author":"Burchert","year":"2020","journal-title":"J Clin Oncol"},{"issue":"9","key":"2022121313282290200_hem2022000358C19","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/S1470-2045(20)30455-1","article-title":"Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial","volume":"21","author":"Xuan","year":"2020","journal-title":"Lancet Oncol"},{"issue":"8","key":"2022121313282290200_hem2022000358C20","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1182\/blood-2018-08-869453","article-title":"Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD","volume":"133","author":"Schlenk","year":"2019","journal-title":"Blood"},{"issue":"18","key":"2022121313282290200_hem2022000358C21","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1056\/NEJMoa1902688","article-title":"Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML","volume":"381","author":"Perl","year":"2019","journal-title":"N Engl J Med"},{"issue":"23","key":"2022121313282290200_hem2022000358C22","doi-asserted-by":"crossref","first-page":"3366","DOI":"10.1182\/blood.2021011583","article-title":"Follow-up of patients with R\/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial","volume":"139","author":"Perl","year":"2022","journal-title":"Blood"},{"issue":"7","key":"2022121313282290200_hem2022000358C23","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/S1470-2045(19)30150-0","article-title":"Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial","volume":"20","author":"Cortes","year":"2019","journal-title":"Lancet Oncol"},{"issue":"19","key":"2022121313282290200_hem2022000358C24","doi-asserted-by":"crossref","first-page":"4945","DOI":"10.1182\/bloodadvances.2020002904","article-title":"Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial","volume":"4","author":"Voso","year":"2020","journal-title":"Blood Adv"},{"issue":"9","key":"2022121313282290200_hem2022000358C25","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/S1470-2045(14)70281-5","article-title":"Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials","volume":"15","author":"Hills","year":"2014","journal-title":"Lancet Oncol"},{"issue":"28","key":"2022121313282290200_hem2022000358C26","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1200\/JCO.20.03048","article-title":"Gemtuzumab ozogamicin improves event-free survival and reduces relapse in pediatric KMT2A-rearranged AML: results from the phase III Children's Oncology Group trial AAML0531","volume":"39","author":"Pollard","year":"2021","journal-title":"J Clin Oncol"},{"issue":"8","key":"2022121313282290200_hem2022000358C27","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1158\/1078-0432.CCR-15-1349","article-title":"Gemtuzumab ozogamicin reduces relapse risk in FLT3\/ITD acute myeloid leukemia: a report from the Children's Oncology Group","volume":"22","author":"Tarlock","year":"2016","journal-title":"Clin Cancer Res"},{"issue":"9825","key":"2022121313282290200_hem2022000358C28","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1016\/S0140-6736(12)60485-1","article-title":"Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study","volume":"379","author":"Castaigne","year":"2012","journal-title":"Lancet"},{"issue":"7","key":"2022121313282290200_hem2022000358C29","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1200\/JCO.2015.62.6846","article-title":"CD33 expression and its association with gemtuzumab ozogamicin response: results from the randomized phase III Children's Oncology Group trial AAML0531","volume":"34","author":"Pollard","year":"2016","journal-title":"J Clin Oncol"},{"issue":"8","key":"2022121313282290200_hem2022000358C30","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1182\/blood.2019003471","article-title":"Mutational profile and benefit of gemtuzumab ozogamicin in acute myeloid leukemia","volume":"135","author":"Fournier","year":"2020","journal-title":"Blood"},{"issue":"23","key":"2022121313282290200_hem2022000358C31","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1200\/JCO.2016.71.2513","article-title":"CD33 splicing polymorphism determines gemtuzumab ozogamicin response in de novo acute myeloid leukemia: report from randomized phase III Children's Oncology Group trial AAML0531","volume":"35","author":"Lamba","year":"2017","journal-title":"J Clin Oncol"},{"issue":"8","key":"2022121313282290200_hem2022000358C32","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1038\/leu.2011.90","article-title":"The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia","volume":"25","author":"Balgobind","year":"2011","journal-title":"Leukemia"},{"issue":"2","key":"2022121313282290200_hem2022000358C33","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/leu.2017.213","article-title":"The MLL recombinome of acute leukemias in 2017","volume":"32","author":"Meyer","year":"2018","journal-title":"Leukemia"},{"issue":"6","key":"2022121313282290200_hem2022000358C34","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.ccell.2019.11.001","article-title":"A menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL- rearranged leukemia","volume":"36","author":"Krivtsov","year":"2019","journal-title":"Cancer Cell"},{"issue":"6477","key":"2022121313282290200_hem2022000358C35","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1126\/science.aax5863","article-title":"Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia","volume":"367","author":"Uckelmann","year":"2020","journal-title":"Science"},{"key":"2022121313282290200_hem2022000358C36","doi-asserted-by":"crossref","article-title":"Safety and efficacy of menin inhibition in patients (Pts) with MLL-rearranged and NPM1 mutant acute leukemia: a phase (Ph) 1, first-in-human study of SNDX-5613 (AUGMENT 101)","author":"Stein","DOI":"10.1182\/blood-2021-146944"},{"issue":"3","key":"2022121313282290200_hem2022000358C37","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.blre.2017.11.001","article-title":"When the good go bad: mutant NPM1 in acute myeloid leukemia","volume":"32","author":"Kunchala","year":"2018","journal-title":"Blood Rev"},{"issue":"6","key":"2022121313282290200_hem2022000358C38","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1182\/blood.2021012806","article-title":"The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML","volume":"139","author":"Heikamp","year":"2022","journal-title":"Blood"},{"issue":"12","key":"2022121313282290200_hem2022000358C39","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1182\/blood-2018-02-791350","article-title":"The rise of apoptosis: targeting apoptosis in hematologic malignancies","volume":"132","author":"Valentin","year":"2018","journal-title":"Blood"},{"issue":"11","key":"2022121313282290200_hem2022000358C40","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0161-5890(02)00252-3","article-title":"The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions","volume":"39","author":"Borner","year":"2003","journal-title":"Mol Immunol"},{"issue":"2","key":"2022121313282290200_hem2022000358C41","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/nm.3048","article-title":"ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets","volume":"19","author":"Souers","year":"2013","journal-title":"Nat Med"},{"issue":"7","key":"2022121313282290200_hem2022000358C42","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and venetoclax in previously untreated acute myeloid leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N Engl J Med"},{"issue":"25","key":"2022121313282290200_hem2022000358C43","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1200\/JCO.20.03736","article-title":"Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed and relapsed or refractory acute myeloid leukemia","volume":"39","author":"DiNardo","year":"2021","journal-title":"J Clin Oncol"},{"issue":"4","key":"2022121313282290200_hem2022000358C44","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S1470-2045(20)30060-7","article-title":"Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study","volume":"21","author":"Karol","year":"2020","journal-title":"Lancet Oncol"},{"issue":"10","key":"2022121313282290200_hem2022000358C45","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/leu.2011.133","article-title":"IDH1 and IDH2 mutations in pediatric acute leukemia","volume":"25","author":"Andersson","year":"2011","journal-title":"Leukemia"},{"issue":"7","key":"2022121313282290200_hem2022000358C46","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1182\/blood.2019002140","article-title":"Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia","volume":"135","author":"Roboz","year":"2020","journal-title":"Blood"},{"issue":"6","key":"2022121313282290200_hem2022000358C47","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1182\/blood-2017-04-779405","article-title":"Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia","volume":"130","author":"Stein","year":"2017","journal-title":"Blood"},{"issue":"1","key":"2022121313282290200_hem2022000358C48","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1097\/MOP.0000000000000856","article-title":"Targeting RAS in pediatric cancer: is it becoming a reality?","volume":"32","author":"Vaseva","year":"2020","journal-title":"Curr Opin Pediatr"},{"issue":"1","key":"2022121313282290200_hem2022000358C49","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1038\/s41467-017-02177-w","article-title":"RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia","volume":"8","author":"Lipka","year":"2017","journal-title":"Nat Commun"},{"issue":"12","key":"2022121313282290200_hem2022000358C50","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1002\/cncr.29986","article-title":"Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies","volume":"122","author":"Borthakur","year":"2016","journal-title":"Cancer"},{"issue":"suppl 1","key":"2022121313282290200_hem2022000358C51","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1182\/blood-2018-99-112955","article-title":"A phase I, first-in-human study evaluating the safety and preliminary antileukemia activity of IMGN632, a novel CD123-targeting antibody-drug conjugate, in patients with relapsed\/refractory acute myeloid leukemia and other CD123-positive hematologic malignancies","volume":"132","author":"Daver","year":"2018","journal-title":"Blood"},{"issue":"3","key":"2022121313282290200_hem2022000358C52","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1080\/10428190701799035","article-title":"Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia","volume":"49","author":"Frankel","year":"2008","journal-title":"Leuk Lymphoma"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2022\/1\/603\/2022913\/603pommert.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2022\/1\/603\/2022913\/603pommert.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T13:29:39Z","timestamp":1670938179000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2022\/1\/603\/493521\/The-evolution-of-targeted-therapy-in-pediatric-AML"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,9]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12,9]]},"published-print":{"date-parts":[[2022,12,9]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2022000358","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,9]]},"published":{"date-parts":[[2022,12,9]]}}}