S881 PREGNANCY OUTCOME IN FEMALE PATIENTS WITH CHRONIC MYELOID LEUKEMIA WORLDWIDE: ANALYSIS OF 305 CASES OF THE EUROPEAN LEUKEMIA NET REGISTRY
Authors: E. Chelysheva, A. Turkina, D. Rea, P. Rousselot, F.E. Nicolini, M.M. Trawinska, A. Romano, M. Malagola, D. Cangemi, I. Dyagil, K. Kotlyarchuk, K. Kazakbaeva, S. Saliev, C. Pavlovsky, B. Moiraghi, D.-W. Kim, H. Klamova, M. Yassin, K. Meliktesyan, G. Mikhailov, P. Ganeva, S. Osorio, M. Mauro, E. Polushkina, R. Shmakov, J. Chabaeva, S. Kulikov, E. Abruzzese
Journal: HemaSphere (2019)

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. Summary/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.