{"doi":"10.1200/jco.23.01911","title":"Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory <i>FLT3</i>-Mutated AML","abstract":"PURPOSE Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML. METHODS This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487 ). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II). RESULTS Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3-ITD measurable residual disease &lt;5 × 10 –5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia–free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort. CONCLUSION The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.","journal":"Journal of Clinical Oncology","year":2024,"id":416382,"datarank":2.687326393445876,"base_score":5.030437921392435,"endowment":5.030437921392435,"self_citation_contribution":0.7545656882088654,"citation_network_contribution":1.9327607052370106,"self_endowment_contribution":0.7545656882088654,"citer_contribution":1.9327607052370106,"corpus_percentile":null,"corpus_rank":null,"citation_count":152,"citer_count":100,"citers_with_citation_signal":78,"citers_with_endowment":78,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9474,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT04140487"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":232840,"name":"Naval Daver","orcid":"0000-0001-7103-373X","position":1,"is_corresponding":false},{"id":109577,"name":"Courtney D. 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Patel","orcid":"0000-0001-5081-2427","position":18,"is_corresponding":false},{"id":1030466,"name":"Regina Abramova","orcid":null,"position":19,"is_corresponding":false},{"id":1200634,"name":"Jennifer Thankachan","orcid":null,"position":20,"is_corresponding":false},{"id":18373,"name":"Marina Konopleva","orcid":"0000-0002-9347-2212","position":21,"is_corresponding":false},{"id":109598,"name":"Hagop M. Kantarjian","orcid":"0000-0002-1908-3307","position":22,"is_corresponding":false},{"id":230403,"name":"Farhad Ravandi","orcid":"0000-0002-7621-377X","position":23,"is_corresponding":false},{"id":230993,"name":"Nicholas J. 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