Safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents: a single-centre, single-arm, phase 2 trial

Abstract

Background: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents.

Methods: We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT02228525.

Findings: Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1-12·2). Two patients did not meet the full eligibility criteria after baseline assessment; therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10-48) in six patients with marrow complete remission, with an additional 12 patients (52%, 95% CI 31-73) achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths.

Interpretation: Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment.

Funding: Karyopharm Therapeutics.

Conflict of interest statement

CONFLICTS OF INTEREST

R.R. reports personal fees from Incyte, personal fees from Celgene, personal fees from Agios, personal fees from Jazz Pharmaceuticals, personal fees from BeyondSpring, personal fees from Apexx, personal fees from Partner Therapeutics, and grants from Stemline and Constellation, outside the submitted work.

J.H.P reports grants and personal fees from Juno Therapeutics, outside the submitted work.

E.M.S. reports personal fees from Agios, personal fees from Celgene, personal fees from Syros, personal fees from GlaxoSmithKline, personal fees from Bayer, personal fees from Auron Therapeutics, outside the submitted work; and has served on advisory boards for Astellas Pharma, Daiichi, Genentech, Novartis, PTC Therapeutics, Agios, Seattle Genetics, Amgen, and Celgene.

M.S.T. reports grants from AbbVie, grants from Cellerant, grants from Orsenix, grants from ADC Therapeutics, grants from Biosight, grants from Glycomimetics, grants from Rafael, grants from Amgen, personal fees from UpToDate, personal fees from AbbVie, personal fees from BioLineRx, personal fees from Daiichi-Sankyo, personal fees from Orsenix, personal fees from KAHR, personal fees from Rigel, personal fees from Nohla, personal fees from Delta Fly Pharma, personal fees from Tetraphase, personal fees from Oncolyze, personal fees from Jazz Pharma, personal fees from Roche, and personal fees from Biosight, outside the submitted work.

O.A.-W. reports grants and personal fees from H3 Biomedicine, personal fees from Foundation Medicine Inc., personal fees from Merck, personal fees from Janssen, personal fees from Envisagenics Inc., and from Daiichi Sankyo, outside the submitted work.

V.M.K. reports clinical trial operational support from Karyopharm, H3 Biomedicine, and GlaxoSmithKline.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Enrollment of patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia refractory to hypomethylating agents into the phase II study of selinexor

Figure 2.. Clinical efficacy of selinexor in hypomethylating agent-refractory MDS.

(A) Swimmer’s plot color-coded by response showing long-lasting responses in two patients and prolonged stable disease in others. Two patients who underwent allogeneic hematopoietic stem cell transplant are marked with boxes. (B) Kaplan-Meier curve showing the survival of all patients and of only the evaluable cohort. mCR = marrow complete response, SD = stable disease, PD= progressive disease, HI-E = haematologic improvement-erythroid, OS = overall survival.