Selinexor in Combination with Venetoclax and Azacitidine for Newly Diagnosed (ND) Unfit Acute Myeloid Leukemia (AML): A Multicenter, Open-Label Prospective Study
Authors: Yang Li , Chen Fangli , Liang Hong , Bai Yunsong , Wu Wenzhong , Yan Xiaojing , Ren Jinhai , Li Si , Yu Yang , Tong Laigen , Pan Deng , Liu Ligen 
Published: December 2023

Introduction:
Acute myeloid leukemia (AML) predominantly affects the elderly, with a median age at diagnosis around 68 years (Bhansali, 2023). Due to existing or potential comorbidities and frailty, many patients are unable to undergo conventional intensive chemotherapy at the time of diagnosis. The combination of venetoclax with azacytidine has shown improved clinical response rates of 64% with a median overall survival of 14.7 months (DiNardo, 2020). However, subgroup data demonstrated no significant benefits in the Chinese population, in pts with poor risk, or in those with TP53 mutations. Therefore, managing AML in elderly or unfit pts remains a significant challenge. Selinexor has shown promising tolerability and clinical activity in AML through various phase 1/2 trials. The triple regimen of selinexor, venetoclax, and azacytidine (SAV) has demonstrated favorable results in AML 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 ND AML pts who are ineligible for intensive therapy.
Methods:
To report the efficacy and safety of ND AML pts ineligible for intensive chemotherapy, treated with a triple regimen from 6 sites. The study enrolled pts who were unfit for intensive chemotherapy, ≥75 years, had significant comorbidities, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥3, organ dysfunction, or had abandoned intensive chemotherapy. The primary study objectives were the complete response (CR)/complete response with incomplete count recovery (CRi) rate and overall response rate (ORR). Responses were assessed according to the ELN2022 criteria.
Pts received the following treatment regimen: 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 CR, CRh, or CRi, as per the center's treatment guidelines, were eligible for transplantation at any time point. Remaining pts continued to receive the SAV regimen until disease progression or intolerable toxicity.
Results:
From March 2023 to the data cutoff on June 10, 2023, a total of 20 pts were enrolled in the study, of which 16 had de novo or therapy-related AML, and 4 had secondary AML with a history of myelodysplastic syndrome. Table 1 displays the baseline characteristics and responses of the newly diagnosed AML pts. The median age of the 20 pts was 64 years (range: 28-80), and the majority of them had high-risk disease: 12/20 (60%) had intermediate-risk, and 8/20 (40%) had adverse-risk according to the ELN 2022 criteria. Additionally, 4/20 (20%) of the pts had therapy-related AML, 6/20 (30%) were aged ≥75 years, 12/20 (60%) had ≥2 high-risk molecular mutations, and a significant proportion had high blast counts.
All pts completed at least 1 cycle of treatment (range: 1-4). Specifically, 1patient completed 4 cycles, 2pts completed 3 cycles, and 7pts completed 2 cycles. The remaining 10pts have just completed their first cycle of treatment and evaluation. With the exception of one patient with disease progression (PD), all other pts are still undergoing treatment. As the treatment duration extends, the depth of remission in pts may further deepen.
The CR/CRi rates and ORR across the ELN 2022 risk groups for all pts, intermediate-risk group, and adverse-risk group were as follows: 80% (16/20) and 90% (18/20), 75% (9/12) and 91.7% (11/12), 87.5% (7/8) and 87.5% (7/8), respectively. In comparison, the VIALE-A data showed a CR/CRi rate of 52.9% for adverse-risk pts, indicating a higher remission rate observed in this study. As of now, 3 pts were MRD-negative.
The reported adverse events of grade 3 or higher occurring in ≥10% of pts in the triple regimen were thrombocytopenia (35%), neutropenia (35%), and infections (15%). The most frequently reported adverse events of Grade 1-2 included anemia, nausea, fatigue, anorexia, and hyponatremia. All adverse events could be managed and improved through dose adjustments and supportive treatment.
Conclusions:
The SAV regimen has been found to be safe and effective, with encouraging complete response (CR) rates in newly diagnosed AML pts, especially in adverse risk patients. Further trial enrollment and correlative analysis are currently underway to thoroughly observe the efficacy and safety of the SAV regimen.