Background: Acute myeloid leukemia (AML) is the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the United States. While complete response rates can be as high as 80% in patients undergoing initial induction chemotherapy, the majority of AML patients will relapse. Refractory or relapsed patients have a bleak prognosis. As there is currently no standard regimen for these patients, a great clinical need exists for new treatment options. Selinexor, an oral first-in-class Selective Inhibitor of Nuclear Export (SINE), inhibits XPO1 mediated nuclear export inducing cytotoxicity in cells with genomic damage. Preclinical data with Ara-C and selinexor significantly prolonged the survival of leukemic mice. A phase I clinical study demonstrated encouraging results in AML patients. The role of selinexor as mono-therapy or in combination is currently under investigation in phase II trials of AML.

Aims: This phase II trial investigates the efficacy & tolerability of Ara-C and Idarubicin in combination with selinexor in patients with relapsed or refractory AML.

Methods: Patients with relapsed/refractory AML were treated with Ara-C (100 mg/m2, continuous infusion, day 1-7), idarubicin (10 mg/m2, day 1, 3, 5) every 4 weeks. Selinexor was administered twice weekly orally starting on day 2 (40 mg/m2). A small cohort of patients received selinexor after registration and before first induction cycle for correlative studies. The primary endpoint was percentage of patients achieving a complete remission or complete remission without normalization of peripheral blood counts (CRi). Secondary endpoints were partial remission rate, percentage of patients undergoing subsequent allogeneic stem cell transplantion, early death rate, overall survival (OS), event-free survival and toxicity.

Results: As of June-16-2015, 21 patients with AML have been enrolled at 3 sites in Germany (NCT02249091) after obtaining informed consent of which 20 had received ≥ 1 induction cycle and were evaluable for efficacy and toxicity. Median age was 60 (range 34-78) years. Seven patients had a complex and 6 a normal karyotype (unknown in 7 cases). On average, patients had received 3.5 (range 1-6) prior therapies. 2 patients had primary refractory disease and 11 patients an early relapse and 7 patients a late relapse. 7 patients had prior allogeneic transplantation.

Overall response rate was 60% (25% of patients achieved CR, 25% of patients achieved CRi, 10% of patients achieved PR). Sixty percent of patients received or were planned for stem cell transplantion or donor lymphocyte infusion. The most frequent non-hematologic AES were vomiting, diarrhoea, nausea, fatigue, anorexia and neutropenic fever. One treatment-related death occurred. The patient developed subarachnoid haemorrhage during thrombocytopenia grade 4 and died.

Summary / Conclusion: The prognosis of relapsed/refractory AML patients is remarkably poor. Our findings suggest that Ara-C and Idarubicin in combination with selinexor resulted in a remarkable response rate and is a promising regimen in this particularly unfavourable cohort of patients without unexpected toxicities enabling the majority of them to proceed to first or second allogeneic stem cell transplantation.


Fiedler:Teva, Amgen, Astellas: Other: Travel Grant; Pfizer, Amgen, Kolltan: Research Funding; Karyopharm: Research Funding. Off Label Use: Selinexor has been used in combination with AraC and idarubicin in relapsed/refractory AML patients.. Chromik:Karyopharm: Research Funding. Theile:GSO Hamburg: Employment. Kranich:GSO Global: Employment. Heuser:Karyopharm: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.

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