Clinical Response and Tolerability of Selinexor in Acute Myeloid Leukemia and Other Hematologic Malignancies - a Systematic Review

Abstract

Introduction Selinexor, a SINE (selective inhibitor of nuclear export) compound, inhibits exportin 1 (XPO1) involved in transport of tumor suppressor proteins leading to apoptosis of tumor cells. XPO1 is overexpressed in variety of cancer including ovarian cancer, pancreatic cancer, glioma, osteosarcoma, leukemia, lymphoma, and multiple myeloma. The aim of this study is to summarize clinical response and adverse events of selinexor in hematological neoplasms. Methods A comprehensive literature search on PubMed, Embase, AdisInsight and Clinicaltrials.gov was completed on July 12, 2018. Studies focusing on efficacy and/or adverse events of selinexor in patients with hematological neoplasms were included for the review. Results Out of 321 studies found on initial search, we finalized 15 studies (8 phase I and 7 phase I/II) after screening by two reviewers. AML: Selinexor in combination with high-dose cytarabine and mitoxantrone has shown overall response rate (ORR) of 70% among 20 patients with acute myeloid leukemia (AML), Wang et al., 2018. Out of 12 newly diagnosed AML (ND AML) patients, 11 (92%) patients showed response with complete response (CR) in 7, CR with incomplete recovery (CRi) in 3 and partial response (PR) in 1 patient. Among 8 relapsed/refractory AML (R/R AML) patients, only 3 patients showed CR while 5 had treatment failure (TF), ORR in this subset was 38%. In 81 evaluable R/R AML patients receiving selinexor as monotherapy only 14% of the patients showed response while 31% patients had disease progression (PD) along with grade ≥3 hematological adverse events (AEs) of thrombocytopenia, anemia and neutropenia in 19%, 15% and 13% patients, respectively (Garzon et al., 2017). MM: Relapsed refractory multiple myeloma patients receiving selinexor combined with pomalidomide and dexamethasone have achieved ORR of 60% with CR in 1 and PR in 5 patients (Chen et al., 2016 n=10) with grade ≥3 neutropenia in 8 patients. In another regimen with doxorubicin and dexamethasone the clinical benefit rate (CBR) was 26% with 15% overall response (Rachid et al., 2017 n=27). Grade ≥3 neutropenia, thrombocytopenia and hyponatremia occurred in 33%, 33% and 30% of patients, respectively. NHL: Kuruvilla et al. observed ORR in 31% patients with relapsed refractory non-Hodgkin lymphoma with single-agent selinexor. Grade ≥3 thrombocytopenia, neutropenia and anemia occurred in 47%, 32% and 27% patients, respectively. The efficacy of selinexor in phase I and I/II clinical trials is given in table 1 while toxicity is mentioned in table 2. With selinexor, the most common hematological and nonhematological AEs noted were thrombocytopenia and hyponatremia, respectively. Conclusion: Selinexor based combination regimens have shown better clinical response against AML as compared to monotherapy. The efficacy results in multiple myeloma and other hematological malignancies are also encouraging. The adverse events like cytopenias were common as in other chemotherapy regimens. Disclosures No relevant conflicts of interest to declare.

XPO1 inhibition with selinexor synergizes with proteasome inhibition in neuroblastoma by targeting nuclear export of IkB

“…Selinexor has a fairly favorable toxicity profile when used clinically in adult patients [37] , though children may be more prone to dose-limiting toxicities. We therefore considered combinatorial treatment strategies to augment selinexor activity without the need for dose escalation.…”