Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Phase I trial of maintenance selinexor after allogeneic hematopoietic stem cell transplantation for patients with acute myeloid leukemia and myelodysplastic syndrome

Bone Marrow Transplantation volume 55, pages 2204–2206 (2020)Cite this article

Subjects

Selinexor is a selective inhibitor of nuclear export that exhibits antitumor activity by preventing nuclear export of tumor suppressor proteins. It is currently approved for use in refractory multiple myeloma [1] and has shown antitumor activity in preclinical models in a wide range of malignancies. In AML, selinexor monotherapy or combination therapy has demonstrated tolerability and overall response rates from 14 to 70% [2,3,4]. Given that survival is dismal when patients relapse after allogeneic stem cell transplant (allo-SCT) in AML and MDS, maintenance therapy offers the possibility of delaying or avoiding disease recurrence [5]. Pharmacologic maintenance therapy has shown promise in improving disease-free survival [6]. Selinexor is orally bioavailable and has shown to be tolerable in studies to date, and therefore represents an attractive maintenance strategy after allo-SCT in AML and MDS. We conducted a phase I trial to define the maximum tolerated dose (MTD) of selinexor given as maintenance therapy after allo-SCT.

This study was approved by the Institutional Review Board, and informed consent was obtained from all patients. The trial was registered at ClinicalTrials.gov (NCT02485535). Patients with AML and MDS underwent allo-SCT and did not have evidence of relapse, active infection, or unresolved transplant-related toxicities at the time of enrollment. Baseline characteristics of the 12 patients are listed in Table 1. Selinexor was initiated between day 60 and 100 (+/− 3 days) after allo-SCT to allow for recovery from the conditioning regimen and other toxicities. Each cycle lasted 28 days, and selinexor was dosed on day 1 of each of 4 weeks for a total of four doses per cycle. Two escalating doses of selinexor were used: 60 mg by mouth (PO) weekly and 80 mg PO weekly. This dosing regimen was continued for 12 cycles if tolerated and if there was no evidence of disease relapse.

Table 1 Clinical characteristics (n = 12).
Full size table

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral selinexor–dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381:727–38.

    Article  CAS  Google Scholar 

  2. Garzon R, Savona M, Baz R, Andreeff M, Gabrail N, Gutierrez M, et al. A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. Blood. 2017;129:3165–74.

    Article  CAS  Google Scholar 

  3. Alexander TB, Lacayo NJ, Choi JK, Ribeiro RC, Pui CH, Rubnitz JE. Phase I study of selinexor, a selective inhibitor of nuclear export, in combination with fludarabine and cytarabine, in pediatric relapsed or refractory acute leukemia. J Clin Oncol. 2016;34:4094–101.

    Article  CAS  Google Scholar 

  4. Fiedler W, Heuser M, Chromik J, Thol F, Bokemeyer C, Theile S, et al. Phase II results of Ara-C and idarubicin in combination with the selective inhibitor of nuclear export (SINE) compound selinexor (KPT-330) in patients with relapsed or refractory AML. Blood. 2016;128:341.

    Article  Google Scholar 

  5. de Lima M, Porter DL, Battiwalla M, Bishop MR, Giralt SA, Hardy NM, et al. Proceedings from the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part III. Prevention and Treatment of Relapse after Allogeneic Transplantation. Biol Blood Marrow Transplant. 2014;20:4–13.

    Article  Google Scholar 

  6. Huls G, Chitu DA, Havelange V, Jongen-Lavrencic M, van de Loosdrecht AA, Biemond BJ, et al. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients. Blood. 2019;133:1457–64.

    Article  CAS  Google Scholar 

  7. Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol. 2005;23:1993–2003.

    Article  Google Scholar 

  8. Huisman C, de Weger RA, de Vries L, Tilanus MG, Verdonck LF. Chimerism analysis within 6 months of allogeneic stem cell transplantation predicts relapse in acute myeloid leukemia. Bone Marrow Transpl. 2007;39:285–91.

    Article  CAS  Google Scholar 

  9. Tyler PM, Servos MM, de Vries RC, Klebanov B, Kashyap T, Sacham S, et al. Clinical dosing regimen of selinexor maintains normal immune homeostasis and T-cell effector function in mice: implications for combination with immunotherapy. Mol Cancer Ther. 2017;16:428–39.

    Article  CAS  Google Scholar 

  10. Weisser M, Kern W, Rauhut S, Schoch C, Hiddemann W, Haferlach T, et al. Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia. 2005;19:1416–23.

    Article  CAS  Google Scholar 

  11. Rautenberg C, Pechtel S, Hildebrandt B, Betz B, Dienst A, Nachtkamp K, et al. Wilms’ tumor 1 gene expression using a Standardized European LeukemiaNet-Certified Assay compared to other methods for detection of minimal residual disease in myelodysplastic syndrome and acute myelogenous leukemia after allogeneic blood stem cell transplantation. Biol Blood Marrow Transplant. 2018;24:2337–43.

    Article  CAS  Google Scholar 

  12. Cilloni D, Renneville A, Hermitte F, Hills RK, Daly S, Jovanovic JV, et al. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol. 2009;27:5195–201.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

HL was supported by UCCCC pilot grant, Cancer Research Foundation Young investigator award and K12 Paul Calabresi award. The work is also supported by the University of Chicago Cancer Center Support Grant (CA014599).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, University of Chicago Medicine, 5841S Maryland Ave, Chicago, IL, 60637, USA

    Jennifer H. Cooperrider

  2. Section of Hematology/Oncology, University of Chicago Medicine, 5841S Maryland Ave, Chicago, IL, 60637, USA

    Noreen Fulton, Richard A. Larson, Wendy Stock, Satyajit Kosuri, Michael Bishop & Hongtao Liu

  3. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, 1500 E. Duarte Road, Duarte, CA, 91010, USA

    Andrew S. Artz

Authors
  1. Jennifer H. Cooperrider
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noreen Fulton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew S. Artz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard A. Larson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wendy Stock
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satyajit Kosuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Bishop
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hongtao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HL designed the trial. ASA, WS, RAL, SK, MB, and HL conducted the clinical trial. JHC, ASA, WS, RAL, SK, MB, and HL collected and analyzed the clinical data. NF processed patient samples and performed WT1 qRT-PCR. JHC conducted the statistical analysis of the clinical results. All authors contributed to the data analysis and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hongtao Liu.

Ethics declarations

Conflict of interest

The trial was sponsored by Karyopharm. HL is the PI of the trial and has research support from Karyopharm and BMS. While several coauthors had research support from other pharmaceutical companies or served as consultant or advisory board members for other pharmaceutical companies, no one has conflict of interest associated with this current study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Presented at: ASH 2017.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cooperrider, J.H., Fulton, N., Artz, A.S. et al. Phase I trial of maintenance selinexor after allogeneic hematopoietic stem cell transplantation for patients with acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant 55, 2204–2206 (2020). https://doi.org/10.1038/s41409-020-0925-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-020-0925-2

This article is cited by

Search

Advanced search

Quick links