A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov , NCT02573363 . Registered October 5, 2015.

Keywords: AML; Induction chemotherapy; Selinexor; XPO1/CRM1.

Conflict of interest statement

Ethics approval and consent to participate

The trial was approved by the Institutional Review Board at The University of Chicago (IRB15-0412) on 9/16/2015. All patients enrolled in the study were consented through a standardized informed consent process.

Consent for publication

Not applicable

Competing interests

Dr. Liu has research support from Karyopharm and Bristol Myers Squibb. The clinical trial was supported by Karyopharm. The co-authors reported research funding and membership on advisory boards from different companies, but reported no conflicts of interest with this study.

Publisher’s Note

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

Figures

Fig. 1

Study schematic. Schematic of phase 1 dose escalation study. Selinexor dosing remained unchanged for all phases, except for 2 patients who received reduced selinexor dosing during consolidation. Twenty patients entered induction, and 14 achieved a response. No patients received a second cycle of induction. No patients withdrew. Six patients entered consolidation, but 1 soon proceeded to allogeneic HCT. Ultimately, 8 underwent allogeneic HCT. One patient quickly relapsed after induction prior to starting the next phase of therapy. HCT = hematopoietic cell transplantation

Fig. 2

Kaplan-Meier curves depicting patient survival and relapse since the start of induction. a Overall patient survival (n = 20). b Relapse-free survival (n = 14)

Fig. 3

WT1 levels at set time points in induction and at relapse. WT1 levels were assessed in bone marrow samples from 8 patients (7 CR/CRi/PR, 1 TF) shown here at the start of induction, at the day 12 nadir, and the end of induction defined as either count recovery or day 56, and at relapse if applicable. WT1 levels were normalized against the control ABL level. a WT1 levels of 7 patients who achieved a response. Screening baseline range 0.03–2.80; day 12 range 0.00–0.02; end of induction range 0.00–0.05. b One patient did not respond and maintained detectable WT1 at all time points (0.20, 0.06, 0.02). c One of the 7 responders displayed in a initially achieved an incomplete response but then relapsed. This patient had detectable WT1 at all time points (0.04, 0.02, 0.05, 0.06 at relapse)

Fig. 4

Immunohistochemistry staining of DNA damage response proteins. a H&E and Ki67 staining from a CR patient (left panels) and a TF patient (right panels) demonstrate characteristic bone marrow morphology and cell proliferation profile. In both CR and TF patient samples collected at baseline, tumor cells actively proliferate as shown by intensive Ki67 staining. In CR patient, complete remission of tumor cells was achieved at day 12 with few dividing cells visible; at recovery stage, high level of Ki67 staining in clustered cells is typical of active hematopoiesis. In TF patient, although complete remission was not achieved, tumor cell density and cell proliferation (Ki67) were significantly reduced in day 12 bone marrow. b Increased nuclear staining of major TSPs p53, SMAD4, Rb, and p21 were demonstrated in bone marrow biopsy samples collected from a TF patient at baseline and at day 12. Less cells stained positive for topoisomerase IIα after induction at day 12, suggesting reduced cell proliferation. Increased phosphorylated γH2A.X (Ser 139) staining after induction indicate more DNA damage at day 12