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Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome

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Abstract

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65–80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1–24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1–6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69–91%) vs. 59% (45–72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl).

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Fig. 1: Consort diagram.
Fig. 2: Overall survival and event-free survival.
Fig. 3: Hematological recovery after cycle 1.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The Authors thank the local and central data managers as well as the HOVON Data center Trial team and Karyopharm for free drug supply.

Funding

Dutch Cancer Foundation for financial support; Karyopharm for financial support and delivery of drug for free.

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writing—original draft preparation, JJWMJ, GO, BL and YvN. All authors have read, commented on and agreed to the published version of the manuscript.

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Correspondence to J. J. W. M. Janssen.

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Conflict of interest

JJWMJ: Research support: Novartis, BMS. President, Apps for Care and Science, nonprofit foundation supported by Abbvie, Alexion, Amgen, Astellas, BMS, Daiichi-Sankyo, Janssen-Cilag, Olympus, Incyte, Sanofi Genzyme, Servier, Jazz, Takeda. Honoraria: Abbvie, Novartis, Pfizer, Incyte. BL: Advisory role with honoraria for AbbVie, Astellas, Bristol Myers Squibb/Celgene, Catamaran Bio, Celgene, AvenCell/GeMoaB, Frame Pharmaceuticals, Gilead, Kronos Bio, Oxford Biomedica, Servier, holding stocks of Frame Pharmaceuticals. YC: consulting fees from MSD, Novartis, Incyte, BMS, Pfizer, Abbvie, Roche, Jazz, Gilead, Amgen, Astra-Zeneca Servier; Travel support from MSD, Roche, Gilead, Amgen, Incyte, Abbvie, Janssen, Astra-Zeneca, Jazz. GJO: Research support: Novartis, J&J, Celgene, Becton Dickinson; Consultancy: J&J, Sunesis, Celgene, Roche; Advisory board: Novartis, Pfizer, BMS, J&J, Sunesis, Celgene, Agios, Amgen, Astellas, Roche, Jazz Pharmaceuticals, Merus. Others: None declared. The funders had no role in the design of the study, nor in the collection, analyses, or interpretation of data, nor in the writing of the manuscript, or in the decision to publish the results.

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Janssen, J.J.W.M., Löwenberg, B., Manz, M. et al. Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome. Leukemia (2022). https://doi.org/10.1038/s41375-022-01657-3

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