{"doi":"10.1002/ajh.70046","title":"Outcomes and Patterns of Relapse of <scp> <i>NPM1</i> </scp> Mutated Acute Myeloid Leukemia Treated With Venetoclax Based Therapies","abstract":"Mutations in nucleophosmin 1 (NPM1-mut) are detected in approximately 30% of newly diagnosed (ND) acute myeloid leukemia (AML), and are considered founder events due to their persistence at relapse [1]. While treatment with both intensive chemotherapy (IC) and low-intensity therapy (LIT) is associated with favorable responses in NPM1-mutated AML, relapses are common, occurring in approximately 50% of IC-treated and more frequently with LIT-treated patients [1, 2]. Recent data suggests that NPM1 wildtype (NPM1-wt) relapses occur in up to 5%–10% of NPM1-mut AML treated with conventional 7+3 chemotherapy [3-5]. This, coupled with the observation that NPM1-mut is a defining event in leukemogenesis which rarely occurs in isolation [6], has raised the question of whether the NPM1-wt relapses represent clonal evolution of a common pre-leukemic stem cell, or a de novo AML arising from a pre-existing, selected clone. We sought to determine the outcomes and patterns of relapse among patients with NPM1-mut AML treated with venetoclax-based therapies and investigate whether these were impacted by treatment intensity. ND patients with NPM1-mut AML treated in one of the following clinical trials were included: fludarabine/cladribine, cytarabine, and idarubicin with venetoclax (FLAG-IDA+VEN/CLIA+VEN [IC+VEN], NCT03214562 [7, 8] and NCT02115295 [9]), cladribine, low dose cytarabine with venetoclax (CLAD+LDAC+VEN, NCT03586609 [10]), and hypomethylating agents with venetoclax (HMA+VEN, NCT03404193 [11] and NCT02203773 [12]). CLIA+VEN initially allowed concurrent FLT3 inhibition, but this was subsequently stopped due to myelosuppression. All other studies did not allow FLT3 inhibitors for patients with FLT3 mutated AML. All patients had bone marrow samples sent for morphology, flow cytometry, cytogenetics, and next-generation sequencing (NGS) with either a 28- or 81-gene panel at diagnosis and relapse. Measurable residual disease (MRD) was assessed via flow cytometry at a sensitivity of 10−4. Response was assessed using the European LeukemiaNet (ELN) 2022 criteria. Overall survival (OS) was defined as the time from treatment initiation to death from any cause. Non-response, relapse, and deaths were considered events for event-free survival (EFS). Landmark analysis used the median time to allogeneic stem cell transplant (SCT) as the landmark. Cumulative incidence of relapse (CIR) was measured in responders from the time of best response to relapse with death as a competing risk and compared with the Fine-Gray test. Statistical analysis was done with R version 4.4.2 (R Foundation, Vienna, Austria). The trials enrolled 516 patients (192 IC+VEN, 190 CLAD+LDAC+VEN, 134 HMA+VEN), of whom 103 (20%) had NPM1-mut (22% of IC+VEN, 18% of CLAD+LDAC+VEN, 19% of HMA+VEN). Baseline and treatment characteristics of the NPM1-mut cohort are shown in Table 1 and depicted in Figure S1. Patients treated with IC+VEN were younger (median 48 years [range, 20–67]) than those treated with CLAD+LDAC+VEN (68 years) or HMA+VEN (72 years). There were no differences between ELN risk stratification and karyotypes between the treatment cohorts. Cytogenetics were diploid in 87%; only one patient had a complex karyotype. Rates of co-mutations were similar between treatment groups. FLT3-ITD was present in 26% of NPM1-mut patients treated with IC+VEN, 11% of CLAD+LDAC+VEN, and 4% of HMA+VEN, with a median allelic ratio of 0.09 (range, < 0.01–0.65). Five patients (median allele ratio 0.4 [range, 0.24–0.65]) in the IC+VEN group received gilteritinib. FLT3-TKD was detected in 19% of the cohort. SCT in first complete remission (CR1) was performed in 64% of IC+VEN, 51% of CLAD+LDAC+VEN, and 8% of HMA+VEN. Indications for SCT included persistent MRD positivity and co-occurring mutations or cytogenetic abnormalities, at the discretion of the treating physician. The overall response rate (ORR) was 99%, with a composite complete remission (CRc) rate of 96%, and MRD-negative CRc in 84%. 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Issa","orcid":"0000-0002-4339-8683","position":6,"is_corresponding":false},{"id":1069202,"name":"Naszrin Arani","orcid":null,"position":7,"is_corresponding":false},{"id":1398350,"name":"Emmanuel Almanza Huante","orcid":null,"position":8,"is_corresponding":false},{"id":232836,"name":"Abhishek Maiti","orcid":"0000-0001-9043-538X","position":9,"is_corresponding":false},{"id":232846,"name":"Guillermo Montalban‐Bravo","orcid":"0000-0002-4533-5176","position":10,"is_corresponding":false},{"id":232842,"name":"Gautam Borthakur","orcid":"0000-0001-7679-6453","position":11,"is_corresponding":false},{"id":230993,"name":"Nicholas J. Short","orcid":"0000-0002-2983-2738","position":12,"is_corresponding":false},{"id":232858,"name":"Sherry Pierce","orcid":"0000-0001-6641-7659","position":13,"is_corresponding":false},{"id":230404,"name":"Elias Jabbour","orcid":"0000-0003-4465-6119","position":14,"is_corresponding":false},{"id":230408,"name":"Guillermo Garcia‐Manero","orcid":"0000-0002-3631-2482","position":15,"is_corresponding":false},{"id":230403,"name":"Farhad Ravandi","orcid":"0000-0002-7621-377X","position":16,"is_corresponding":false},{"id":109598,"name":"Hagop M. Kantarjian","orcid":"0000-0002-1908-3307","position":17,"is_corresponding":false},{"id":109577,"name":"Courtney D. DiNardo","orcid":"0000-0001-9003-0390","position":18,"is_corresponding":false},{"id":232841,"name":"Tapan M. Kadia","orcid":"0000-0002-9892-9832","position":19,"is_corresponding":false},{"id":1067878,"name":"Wei‐Ying Jen","orcid":"0000-0002-9339-3362","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-19T02:50:12.083054Z","pmid":"40874710","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}