A PHASE II STUDY OF SELINEXOR PLUS CYTARABINE AND IDARUBICIN IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (AML)
Author(s): ,
Walter Fiedler
Affiliations:
Hubertus Wald University Cancer Center,University Medical Center Hamburg-Eppendorf,Hamburg,Germany
,
Joerg Chromik
Affiliations:
Medical Clinic II,University Hospital Frankfurt,Frankfurt,Germany
,
Stefanie Amberg
Affiliations:
GSO Global Clinical Research B.V.,Amsterdam,Netherlands
,
Maxim Kebenko
Affiliations:
Hubertus Wald University Cancer Center,University Medical Center Hamburg-Eppendorf,Hamburg,Germany
,
Felicitas Thol
Affiliations:
Dept. of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School,Hannover,Germany
,
Vera Schlipfenbacher
Affiliations:
Medical Clinic II,University Hospital Frankfurt,Frankfurt,Germany
,
Anne Christine Wilke
Affiliations:
Medical Clinic II,University Hospital Frankfurt,Frankfurt,Germany
,
Franziska Modemann
Affiliations:
Hubertus Wald University Cancer Center,University Medical Center Hamburg-Eppendorf,Hamburg,Germany
,
Melanie Janning
Affiliations:
Hubertus Wald University Cancer Center,University Medical Center Hamburg-Eppendorf,Hamburg,Germany
,
Hubert Serve
Affiliations:
Medical Clinic II,University Hospital Frankfurt,Frankfurt,Germany
,
Arnold Ganser
Affiliations:
Dept. of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School,Hannover,Germany
,
Carsten Bokemeyer
Affiliations:
Hubertus Wald University Cancer Center,University Medical Center Hamburg-Eppendorf,Hamburg,Germany
,
Susann Theile
Affiliations:
GSO GmbH,Hamburg,Germany
,
Ute Deppermann
Affiliations:
GSO Global Clinical Research B.V.,Amsterdam,Netherlands
,
Anne Kranich
Affiliations:
GSO GmbH,Hamburg,Germany
Michael Heuser
Affiliations:
Dept. of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School,Hannover,Germany
EHA Library. Fiedler W. Jun 15, 2019; 267463; S880
Walter Fiedler
Walter Fiedler
Contributions
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Abstract

Abstract: S880

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:00 - 17:15

Location: Elicium 2

Background
Patients with relapsed/refractory (R/R) AML have a dismal prognosis. Currently, no salvage chemotherapy regimen has gained universal acceptance. Selinexor, an oral inhibitor of the nuclear export protein exportin-1 (XPO-1), is blocking the transport of tumor suppressor and growth regulatory proteins from the nucleus and has shown encouraging activity in AML. Based on these findings, we initiated a study combining selinexor with standard chemotherapy in patients with acute AML.

Aims
The primary objectives were to determine the objective response rate, the percentage of patients receiving consecutive allogeneic stem cell transplantation (SCT), overall, event-free and relapse-free survival (OS, EFS, RFS) and safety of selinexor in combination with cytarabine and idarubicin. The severity of side effects was recorded according to CTCAE v4.0.

Methods
Patients with R/R AML were treated with cytarabine 100 mg/m² on days 1-7 and idarubicin 10 mg/m² on days 1, 3 and 5 after they had provided written informed consent. Two dose schedules of selinexor were administered in combination with chemotherapy: The initial selinexor dose was 40 mg/m² administered twice weekly for four weeks. Due to prolonged aplasia, a high rate of febrile neutropenia and grade 3/4 diarrhea the selinexor dose was reduced to 60 mg flat dosing twice weekly for 3 weeks after inclusion of 27 patients. For patients not being transplanted after the first or second induction cycle, one year of selinexor monotherapy could be administered as maintenance.

Results
Forty-two patients with a median age of 59.5 years were enrolled. Seventeen patients had received prior SCT. Eleven patients had secondary or therapy-induced AML. Nine patients (21.4%) achieved a complete remission (CR), 11 patients (26.2%) a morphologic CR with incomplete blood count recovery (CRi) and one patient (2.4%) a morphologic leukemia-free state after the first induction cycle resulting in an overall response rate of 50.0%. Eight of 17 patients (47%) with relapse after prior SCT achieved a CR/CRi. Interestingly, 3 out of 4 patients with nucleophosmin 1 (NPM1) mutation responded. Fifteen patients (36%) had a first or second SCT. After a median follow-up of 8.2 months, the median EFS, RFS and OS was 4.9, 17.7 and 8.2 months, respectively. Most commonly reported treatment-emergent adverse events (TEAEs) were nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), and anemia (60%). Most commonly reported grade 3/4 TEAEs were febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). The reduction of selinexor to a flat dose resulted in a reduction of febrile neutropenia from 85% to 33%, and of severe diarrhea from 56% to 40%. Eight patients (19%) discontinued treatment due to TEAEs (diarrhea, nausea, decreased appetite, fatigue, and vomiting). 25 patients (60%) died during the course of the study due to progressive leukemia (12 patients), infectious complications (6 patients), graft-versus-host-disease (2 patients), asystole, multiple brain infarct, and multi-organ failure. Two further deaths were possibly related to selinexor: suspected hemophagocytosis and systemic inflammatory response syndrome.

Conclusion
Selinexor with cytarabine and idarubicin results in a high remission rate in patients with R/R AML with unfavorable risk factors and should be further studied in a larger, randomized phase III trial.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Clinical trial, Refractory

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