A randomized phase II study of selinexor added to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML).

Abstract

6512 Background: Preclinical and early clinical data suggest that inhibition of nuclear export by the XPOI inhibitor selinexor may enhance chemosensitivity in AML. We conducted a randomized phase II study evaluating the addition of selinexor to standard intensive induction and consolidation chemotherapy. Methods: This was an open-label, randomized (3:1) phase II trial in adults with newly diagnosed non-APL, AML. Good risk patients, those with FLT3 mutations or those with an indication for CPX-351 were excluded. Patients were assigned to standard induction with cytarabine and an anthracycline (7+3) followed by high-dose cytarabine (HDAC) consolidation (control arm) or the same regimen with the addition of selinexor (study arm). Selinexor was administered at a fixed dose of 60 mg orally on days 1, 3, 8, 10, 15, and 17 during induction and consolidation cycles. Randomization was not stratified. The primary endpoint was overall survival, analyzed in the intention-to-treat population. Secondary endpoints included overall response rate, complete remission with or without complete count recovery and safety. Results: A total of 57 patients were randomized (study arm n = 43; control arm n = 14). The study was discontinued early after results of the PARADIGM study raised concerns regarding the use of intensive chemotherapy in intermediate- and poor-risk AML patients. Baseline characteristics except for gender were generally balanced (Table 1). Median overall survival was 991 days in the study arm compared with 649 days in the control arm (log-rank p = 0.2267). Thirty-day mortality occurred in 5 patients (11.6%) in the study arm and 2 patients (14.3%) in the control arm. The response rate was 77% (33/43) in the study arm and 50% (7/14) in the control arm, corresponding to a risk ratio of 1.53 (95% CI, 1.01–4.57); this difference did not reach statistical significance by Fisher’s exact test (p = 0.09). The addition of selinexor was feasible, with early mortality rates consistent with intensive induction therapy and no unexpected safety signals observed. Conclusions: In this randomized phase II study, the addition of selinexor to standard induction and consolidation chemotherapy was associated with numerically higher response rates and longer median overall survival compared with chemotherapy alone. Small study size and early termination limit definitive conclusions. However, these findings suggest biological activity of nuclear export inhibition in AML and support further evaluation of selinexor-containing combinations. Clinical trial information: NCT02835222 . Characteristic Control arm (n = 14) Study arm (n = 43) Median age, years (range) 69 (22–75) 65 (24–73) Female sex, n (%) 11 (78.6%) 17 (39.5%) ELN 2022 Risk group  Good 5 (35.7%) 9 (20.9%)  Intermediate 3 (21.4%) 20 (46.5%)  Poor 6 (42.9%) 14 (32.6%)