Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents.
We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito).
Three (15%) patients received the initial dose of 60 mg of selinexor (~ 35 mg/m2), and 17 (85%) received the target level of 80 mg (~ 50 mg/m2). No dose-limiting toxicities were observed. Common adverse events included febrile neutropenia (70%), diarrhea (40%), anorexia (30%), electrolyte abnormalities (30%), bacteremia (25%), cardiac toxicities (25%), fatigue (25%), and nausea/vomiting (25%). None were unexpected given the HiDAC/Mito regimen. Serious adverse events occurred in 6 (30%) patients; one was fatal. Ten (50%) patients achieved a complete remission (CR), 3 (15%) achieved CR with incomplete recovery (CRi), 1 (5%) achieved partial remission (PR), and 6 (30%) had progressive disease for an overall response rate (ORR) of 70%. Eight of 14 (57%) responders proceeded to allogeneic stem cell transplantation. Correlative studies of WT1 levels showed persistently detectable levels in patients who either did not respond or relapsed quickly after induction.
The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses of 80 mg/day (~ 50 mg/m2/day) twice weekly. The recommended phase II dose is 80 mg and warrants further study in this combination.
Howlader N, Noone A, Krapcho M, et al. SEER cancer statistics review, 1975-2014. Bethesda: National Cancer Institute; 2017. https://seer.cancer.gov/csr/1975_2014/. Accessed 1 Jan 2017
Goldstone AH, Burnett AK, Wheatley K, Smith AG, Michael Hutchinson R, Clark RE. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98(5):1302–11. https://doi.org/10.1182/blood.V98.5.1302. CrossRefPubMed
Anderson JE, Kopecky KJ, Willman CL, et al. Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood. 2002;100(12):3869–76. https://doi.org/10.1182/blood-2001-12-0354. CrossRefPubMed
Ishizawa J, Kojima K, Hail N, Tabe Y, Andreeff M. Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein. Pharmacol Ther. 2015;153:25–35. https://doi.org/10.1016/j.pharmthera.2015.06.001. CrossRefPubMedPubMedCentral
Senapedis WT, Baloglu E, Landesman Y. Clinical translation of nuclear export inhibitors in cancer. Semin Cancer Biol. 2014;27:74–86. https://doi.org/10.1016/j.semcancer.2014.04.005. CrossRefPubMed
Das A, Wei G, Parikh K, Liu D. Selective inhibitors of nuclear export (SINE) in hematological malignancies. Exp Hematol Oncol. 2015;4:7. https://doi.org/10.1186/s40164-015-0002-5.
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(34):4094–101. https://doi.org/10.1200/JCO.2016.67.5066. CrossRefPubMedPubMedCentral
Ranganathan P, Kashyap T, Yu X, et al. XPO1 inhibition using selinexor synergizes with chemotherapy in acute myeloid leukemia by targeting DNA repair and restoring topoisomerase II to the nucleus. Clin Cancer Res. 2016;22(24):6142–52. https://doi.org/10.1158/1078-0432.CCR-15-2885. CrossRefPubMedPubMedCentral
Devemy E, Li B, Tao M, et al. Poor prognosis acute myelogenous leukemia: 3—biological and molecular biological changes during remission induction therapy. Leuk Res. 2001;25(9):783–91. https://doi.org/10.1016/S0145-2126(01)00032-7. CrossRefPubMed
Larson SM, Campbell NP, Huo D, et al. High dose cytarabine and mitoxantrone: an effective induction regimen for high-risk acute myeloid leukemia (AML). Leuk Lymphoma. 2012;53(3):445–50. https://doi.org/10.3109/10428194.2011.621562. CrossRefPubMed
Miyawaki S, Hatsumi N, Tamaki T, et al. Prognostic potential of detection of WT1 mRNA level in peripheral blood in adult acute myeloid leukemia. Leuk Lymphoma. 2010;51(10):1855–61. https://doi.org/10.3109/10428194.2010.507829. CrossRefPubMed
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21(24):4642–9. https://doi.org/10.1200/JCO.2003.04.036. CrossRefPubMed
Zhang W, Ishizawa J, Mu H, Daver N, Ruvolo V. Combinatorial targeting of XPO1 and FLT3-ITD exerts synergistic anti-tumor effects in FLT3-mutated acute myeloid leukemias. Blood. 2015;126(23):Abstract 1266. http://www.bloodjournal.org/content/126/23/1266
Nowicki M, Ostalska-Nowicka D, Mikowiak B. Prognostic significance of Ki67-negative blast cell clone in the high risk group of children treated for acute myeloid leukaemia. Folia Histochem Cytobiol. 2006;44(1):49–52. PubMed
Gurion R, Belnik-Plitman Y, Gafter-Gvili A, et al. Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia. In: Raanani P, editor. Cochrane database of systematic reviews. Chichester: John Wiley & Sons, Ltd; 2012. p. CD008238. https://doi.org/10.1002/14651858.CD008238.pub3.
Fiedler W, Heuser M, Chromik J, 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(22):Abstract 341. http://www.bloodjournal.org/content/128/22/341. Accessed 5 Aug 2017
Abdul Razak AR, Mau-Soerensen M, Gabrail NY, et al. First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors. J Clin Oncol. 2016;34(34):4142–50. https://doi.org/10.1200/JCO.2015.65.3949. CrossRefPubMedPubMedCentral
Kuruvilla J, Byrd JC, Flynn JM, et al. The oral selective inhibitor of nuclear export (SINE) selinexor (KPT-330) demonstrates broad and durable clinical activity in relapsed /refractory non Hodgkin’s lymphoma (NHL). Blood. 2014;124(21):396. http://www.bloodjournal.org/content/124/21/396. Accessed 1 Feb 2017
Etchin J, Berezovskaya A, Conway AS, et al. KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells. Leukemia. 2016;31(April):1–8. https://doi.org/10.1038/leu.2016.145.
- A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia
Amy Y. Wang
Richard A. Larson
Andrew S. Artz
Michael R. Bishop
Lucy A. Godley
Michael J. Thirman
Jane E. Churpek
- BioMed Central
Neu im Fachgebiet Onkologie
e.Med Kampagnen-Visual, Mail Icon II