The Efficacy and Safety of the Combination Therapy of Decitabine, Venetoclax， and Selinexor (DVS) for Newly Diagnosed Unfit AML and MDS, and Relapsed/ Refractory AML and High-Risk MDS - a Multicenter, Single Arm, Prospective Clinical Study

Abstract

Selinexor is an oral, reversible, potent Selective Inhibitor of Nuclear Export / SINE ^TM compound that specifically blocks the protein Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1). Selinexor induces cell cycle arrest, inhibits DNA damage repair and modulates the expression of NF-κB in cancer cells lines and has demonstrated broad activity across several hematologic malignancies including AML. In preclinical studies, AML cells, when treated with selinexor, exhibited sensitivity to chemotherapy, in part, by blocking the nuclear export of topoisomerase II (Clin Cancer Res 2016;22(24):6142-6152). This, when coupled with the presence of an anthracycline antibiotic, resulted in an increased number of DNA strand breaks. In May 2019, the FDA approved the use of selinexor in combination with dexamethasone for adults with relapsed or refractory multiple myeloma who received at least four prior therapies with disease refractory to at least two immunomodulatory agents, at least two proteasome inhibitors, and a CD38-targeting monoclonal antibody.

The aim of this study is to evaluate the efficacy and safety of the combination therapy of Decitabine, Venetoclax， and Selinexor (DVS) in the treatment of newly diagnosed AML and MDS patients who are not suitable for intensified chemotherapy, as well as in patients with relapsed/refractory AML and high-risk MDS.

Method: This multicenter, single arm, prospective clinical study conducted at multiple research centers in China. A total of 96 patients will be enrolled in the study. The patients were treated with Decitabine 20 mg/m², d1-5；Venetoclax 100 mg d1, 200 mg d2, 400 mg d3-21; Selinexor 60 mg/d, d4, 11, 18. Every 28 days are one cycle. The primary endpoints are complete remission(CR)/complete remission with incomplete count recovery (CRi) / incomplete recovery of peripheral blood cell count/ANC>0.5X10⁹/L (500/uL) and platelet count ≥ 50 × 10⁹/L (50000/uL), meeting other CR criteria(CRh)/ morphologic leukemia-free state (MLFS) (CR/CRI/CRh/MLFS). Secondary endpoints include objective response rate (ORR) (complete response rate/incomplete recovery of peripheral blood cell count, partial response rate) ，safety.

Result: Until July, 2024, there are 14 patients(AML/MDS：12/2) included this study. The median age of the patients is 63.5（24-76）years. The male and female are 5 and 9. Among them, The median of white blood cell count (WBC) is 3.3×10^9/L, platelet count (Platelets) is 41.5×10⁹/L, and the percentage of blast cells in bone marrow is 29.25%. During the first course of treatment, 2 patients discontinued the treatment due to adverse events. 9 patients were evaluated for efficacy, the other three cases did not enter the first course of evaluation due to short follow-up time.

With a median follow-up of survivors of 40(27-117) days, 9 patients' efficacy can be evaluated. The complete remission rate was 55.56%（5/9），One （11.11%）patient has stable disease. Five patients experienced adverse events, including two cases of pulmonary infection, one case of thrombocytopenia, one case of pancytopenia, and one case of diarrhea. All were mild or moderate in severity.

Conclusion：Combination therapy of Decitabine, Venetoclax，and Selinexor (DVS) has a manageable safety profile and showed activity in AML and MDS.

No relevant conflicts of interest to declare.

Selinexor is an oral, reversible, potent Selective Inhibitor of Nuclear Export / SINE ^TM compound that specifically blocks the protein Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1). Selinexor induces cell cycle arrest, inhibits DNA damage repair and modulates the expression of NF-κB in cancer cells lines and has demonstrated broad activity across several hematologic malignancies including AML. In preclinical studies, AML cells, when treated with selinexor, exhibited sensitivity to chemotherapy, in part, by blocking the nuclear export of topoisomerase II (Clin Cancer Res 2016;22(24):6142-6152). This, when coupled with the presence of an anthracycline antibiotic, resulted in an increased number of DNA strand breaks. In May 2019, the FDA approved the use of selinexor in combination with dexamethasone for adults with relapsed or refractory multiple myeloma who received at least four prior therapies with disease refractory to at least two immunomodulatory agents, at least two proteasome inhibitors, and a CD38-targeting monoclonal antibody.The aim of this study is to evaluate the efficacy and safety of the combination therapy of Decitabine, Venetoclax， and Selinexor (DVS)  in the treatment of newly diagnosed AML and MDS patients who are not suitable for intensified chemotherapy, as well as in patients with relapsed/refractory AML and high-risk MDS.