Selinexor in combination with venetoclax and azacitidine for newly diagnosed (ND) unfit Acute Myeloid Leukemia (AML): A multicenter, open-label prospective study

Abstract

Abstract Introduction： The triple regimen of selinexor, venetoclax, and azacytidine (SAV) has demonstrated favorable results in AML patients (pts) with severe co-morbidities in real-world settings. To further evaluate its efficacy and safety, we have designed a prospective study (NCT05736965) to assess the SAV regimen for newly diagnosed (ND) AML pts who are ineligible for intensive therapy. The promising results of the first 20 patients were presented orally at the 65th ASH meeting in 2023. Here, We would like to present the updated results of the novel triple (SAV) regimen at the coming ASH annual meeting. Methods： The primary study endpoint is the composite complete remission rate (CRc) which included complete remission (CR), complete remission with partial hematological recovery (CRh) and complete response with incomplete hematological recovery (CRi) according to the ELN2022 criteria. The triple SAV regimen is listed as below: Selinexor 60mg on days 3, 10, and 17; Azacitidine 75mg/m2 on days 1-3, 8-9, and 15-16; Venetoclax 100mg on day 1, 200mg on day 2, and 400mg on days 3 to 14. Each treatment cycle lasted for 28 days. Pts who achieved CRc, were eligible for transplantation at any time point as per the center's treatment guidelines. Remaining pts continued to receive the SAV regimen or other consolidation and/or maintenance therapy based on the investigator's decisions until disease progression or intolerable toxicity. Results: As of July, 2025, a total of 53 pts was enrolled in the study. Eighty-nine percent (47/53, 89%) pts were diagnosed as de novo AML, and 6/53(11%) pts were diagnosed as secondary AML. Two pts had extramedullary infiltration (one with central nervous system involvement, and the other with cutaneous involvement). The median age of the 53 pts was 66 years (range: 28-83), and 12/53 (23%) were aged ≥75 years. Sixty-six percent (35/53, 66%) had intermediate-risk, and 18/53 (34%) had adverse-risk according to the ELN 2022 criteria. Additionally, a significant proportion had high blast counts: 22/53 (42%) had concomitant ≥50% bone marrow blast counts at diagnosis. With the exception of patients with disease progression (PD) or receiving hematopoietic stem cell transplantation, all of other pts are still undergoing treatment. Except for 1 pt undergoing cycle 1 therapy and 1 pt who died during cycle 1 therapy, the remaining 51 pts underwent at least one efficacy evaluation. The CRc rates and ORR across the ELN 2022 risk groups for all pts, intermediate-risk group, and adverse-risk group were as follows: 80% (41/51), 79% (26/33), 83% (15/18) and 90% (46/51), 91% (30/33), 89% (16/18), respectively. As of now, 25 pts achieved the best efficacy of MRD-negative. Two pts with extramedullary disease achieved MRD-negative status following SAV regimen therapy. Regrettably, one died due to post-transplant complications, while disease relapse occurred in the other due to a delay in transplantation timing resulting from non-treatment-related factors. One pt with a TP53 mutation achieved CRh after treatment. Five pts enrolled with co-occurring FLT3-ITD, DNMT3A, and NPM1 mutations, 4 pts achieved CR/CRi. As for the reported adverse events of grade 3 or higher, the top two ranked in hematologic toxicity were neutropenia (70%) and thrombocytopenia (41%), the top two for non-hematologic toxicity were infections (30%) and asthenia (30%). All adverse events could be managed and improved through supportive treatment. Conclusions： SAV regimen has been found to be safe and effective, with encouraging CRc rates in newly diagnosed unfit AML pts, especially in adverse risk subgroup. The triple regimen by adding selinexor to azacitidine plus venetoclax protocol show more efficacy and similar adverse effect.