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The dysregulation of tumor suppressor proteins (TSPs) and other proteins regulating growth are crucial for the tumorigenesis of acute myeloid leukemia (AML). TSPs require nuclear localization to function, and excess nuclear export of critical TSPs can lead to their functional inactivation in tumor cells. Selinexor, a first-in-class, selective inhibitor of nuclear export is a novel agent that can block Exportin 1 (XPO1), allowing for accumulation of TSPs in the nucleus, eventually leading to cell cycle arrest and apoptosis. Therefore, Abboud and Chendamarai, Washington University School of Medicine in St. Louis, St. Louis, US, and colleagues initiated a preclinical and phase I/II study (NCT02416908) to examine the efficacy and safety of selinexor in combination with chemotherapy for the treatment of relapsed or refractory (R/R) AML. The results of the study were published in Haematologica in November 2019.1
Based on the preclinical data, an open-label, phase I/II study commenced of selinexor combined with cladribine, cytarabine, and granulocyte-colony stimulating factor (G-CSF; CLAG) regimen for the treatment of patients with R/R AML. The study enrolled 40 patients (Table 1) between June 6, 2015 and January 28, 2018
Age, years (median, range) | 55.5 (21–70) |
Female gender (%) | 37.5 |
Status at study entry (%) | |
---|---|
Primary refractory disease following 2 or less cycles of induction chemotherapy | 30 |
First relapse with no prior unsuccessful salvage chemotherapy | 67.5 |
R/R to hypomethylating agent | 2.5 |
Cytogenetic risk (%) | |
Favorable | 5.0 |
Intermediate | 67.5 |
Poor | 22.5 |
Not available | 5.0 |
R/R, relapsed/refractory |
The investigators concluded that the results from this study show that selinexor in combination with CLAG is an anthracycline-free regimen which has a manageable safety and acceptable efficacy profile in patients with R/R AML. It may, therefore, be potentially used as a bridge to allogeneic hematopoietic cell transplantation in some patients.
Adverse events, such as gastrointestinal toxicity and prolonged thrombocytopenia, were seen with selinexor treatment, which is consistent with results from other studies using selinexor. According to the investigators, the rate of gastrointestinal and hematopoietic side effects can be considered low, probably due to the fact that selinexor was given at a relatively low, flat dose of 60 mg twice weekly and supportive premedication with 5-HT3 antagonists and dexamethasone was provided to all patients.
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