{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T02:04:45Z","timestamp":1788746685867,"version":"build-2803163510"},"reference-count":85,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Recent implementations with novel target drugs of the hypomethylating agent\/venetoclax doublet challenge our treatment approach in acute myeloid leukemia patients ineligible for intensive chemotherapy. Given the doublets\u2019 efficacy, associations of agents based on the disease\u2019s biology to the doublet backbone are leading to novel triplet (or more) combinations. In the present review mainly FLT3, IDH and KMT2A are discussed as possible targets in this context. These triplets do not only have efficacy in relapsed\/refractory patients but also in treatment-na\u00efve patients. Results from concluded and ongoing clinical trials, as well as real-world experiences, report high efficacies competing with intensive chemotherapy. For instance, the azacytidine\/venetoclax\/gilteritinib triplet as first-line is reported to induce a complete remission rate with and without incomplete recovery (CR\/CRi) of 96%, with 90% of responders achieving minimal residual negativity. Once a stable CR was obtained, 47% of patients who were initially considered too frail for intensive chemotherapy were able to undergo allogeneic stem cell transplantation. However, there are still open questions and challenges regarding toxicity, post-remission therapy, and overall treatment duration. The present review will not only present the specific potency of these arising triplets, but also discuss their challenges and limitations, based on currently available data. Besides regimens containing approved inhibitors, triplets with next-generation inhibitors, including completely orally administered triplet regimens, are also summarized. Their promising results are leading to advanced phase clinical studies by international consortia and collaborative groups, aiming to further refine their clinical management.<\/jats:p>","DOI":"10.3390\/cancers18040615","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T10:52:21Z","timestamp":1770979941000},"page":"615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hypomethylating Agents and Venetoclax Based Triplets Targeting FLT3, IDH and KMT2A in Acute Myeloid Leukemia: Current Studies and Challenges of a Tailored Approach"],"prefix":"10.3390","volume":"18","author":[{"given":"Elisa","family":"Santambrogio","sequence":"first","affiliation":[{"name":"Division of Hematology and Allogeneic Stem Cell Transplant Unit, A.O.U. Citt\u00e0 della Salute e della Scienza di Torino, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1922-9054","authenticated-orcid":false,"given":"Alessia","family":"Castellino","sequence":"additional","affiliation":[{"name":"Department of Hematology, AO Santa Croce e Carle, 12100 Cuneo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesta","family":"Audisio","sequence":"additional","affiliation":[{"name":"Division of Hematology and Allogeneic Stem Cell Transplant Unit, A.O.U. Citt\u00e0 della Salute e della Scienza di Torino, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Rheumatology, Immunoncology and Stem-Cell Transplantation, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Feldmann","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Rheumatology, Immunoncology and Stem-Cell Transplantation, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raheel","family":"Iftikhar","sequence":"additional","affiliation":[{"name":"Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center\/National Institute of Blood and Marrow Transplant, Rawalpindi 46000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Brossart","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Rheumatology, Immunoncology and Stem-Cell Transplantation, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Semra","family":"Aydin","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Rheumatology, Immunoncology and Stem-Cell Transplantation, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1158\/2159-8290.CD-16-0313","article-title":"Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia","volume":"6","author":"Konopleva","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.ccr.2006.10.006","article-title":"Mechanisms of Apoptosis Sensitivity and Resistance to the BH3 Mimetic ABT-737 in Acute Myeloid Leukemia","volume":"10","author":"Konopleva","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1182\/blood-2018-03-828269","article-title":"BCL-2 Inhibition in AML: An Unexpected Bonus?","volume":"132","author":"Konopleva","year":"2018","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1158\/1078-0432.CCR-19-1900","article-title":"5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis","volume":"26","author":"Jin","year":"2020","journal-title":"Clin. 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