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Selinexor and Venetoclax Combination in Patients With Relapsed or Refractory Acute Myeloid Leukemia
Somedeb Ball1,2, Farrukh T Awan3, Ben K Tomlinson4
1Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Abstract:
Preclinical studies showed a synergistic antileukemia activity with combination of selective XPO1 inhibitor selinexor (SEL) and venetoclax (VEN), with potential to overcome VEN resistance by reducing the anti-apoptotic protein MCL1. In an investigator-sponsored, open-label, phase Ib study (NCT03955783), adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) were enrolled. After the dose-escalation phase, SEL 80 mg po weekly plus VEN 400 mg/day following ramp-up was deemed the recommended phase II dose. Responses were assessed with IWG2003 and ELN 2022 criteria. Nineteen patients with R/R AML were enrolled. Median age at enrollment was 67.2 (range, 21.1-83.8) years. Overall, patients received median of 3 (range, 1-5) prior lines of therapy. The most common grade 3-5 treatment emergent adverse events (TEAE) were anemia (39%), neutropenia (33%), febrile neutropenia (28%), and thrombocytopenia (28%). Overall, the response rate with SEL-VEN was 21%. Two (11%) patients, one with prior allo-HSCT and one with prior VEN and both treated with SEL 80 mg/week, experienced complete remissions, with duration of response of 7 and 9.1 months, respectively. After a median follow up of 3.0 (range, 0.6-15.4) months, median event-free survival was 2.4 (95% CI: 1.9-12.1) months and median overall survival was 6.4 (95% CI: 2.5-12.1) months. In conclusion, SEL-VEN was feasible and active in a heavily pretreated AML cohort, with no new toxicity signal, but survival outcomes remained poor. The second-generation XPO1-inhibitor eltanexor, combined with VEN may further improve outcomes in VEN resistant AML in an ongoing study (NCT06399640).
Insights
The combination of selinexor (SEL) and venetoclax (VEN) showed feasibility and activity in relapsed/refractory acute myeloid leukemia (R/R AML). While responses were observed, overall survival outcomes remained poor, suggesting a need for improved therapeutic strategies in R/R AML.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Preclinical data suggest selinexor (SEL) and venetoclax (VEN) have synergistic antileukemia activity in acute myeloid leukemia (AML).
- SEL may overcome VEN resistance by downregulating the anti-apoptotic protein MCL1.
- Venetoclax resistance is a significant challenge in treating relapsed or refractory AML (R/R AML).
Purpose of the Study:
- To evaluate the safety and efficacy of SEL in combination with VEN in adult patients with R/R AML.
- To determine the recommended Phase II dose for SEL plus VEN in this patient population.
- To assess response rates, duration of response, event-free survival, and overall survival.
Main Methods:
- An investigator-sponsored, open-label, Phase Ib study (NCT03955783) enrolled adult patients with R/R AML.
- A dose-escalation phase determined the recommended Phase II dose of SEL 80 mg weekly plus VEN 400 mg/day.
- Responses were assessed using IWG2003 and ELN 2022 criteria.
Main Results:
- Nineteen R/R AML patients were enrolled, with a median age of 67.2 years and a median of 3 prior lines of therapy.
- The overall response rate was 21%, with two patients achieving complete remissions (duration 7 and 9.1 months).
- Common Grade 3-5 treatment-emergent adverse events included anemia (39%), neutropenia (33%), febrile neutropenia (28%), and thrombocytopenia (28%). Median event-free survival was 2.4 months and median overall survival was 6.4 months.
Conclusions:
- The combination of SEL and VEN is feasible and demonstrates activity in heavily pretreated R/R AML patients.
- No new safety signals were identified with the SEL-VEN combination.
- Survival outcomes remain poor, highlighting the need for novel therapeutic approaches, potentially involving next-generation XPO1 inhibitors like eltanexor with VEN.
