Selinexor Maintenance Is Feasible and Tolerable after Allogeneic Stem Cell Transplant (allo-SCT) for Patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Background: Selinexor, an exportin 1 (XPO1) inhibitor, has demonstrated anti-leukemic effects as a single agent in relapsed/refractory AML. We hypothesized that selinexor could be used as maintenance therapy after allo-SCT to prevent disease relapse in patients with AML and MDS.

Methods: This phase I trial tests selinexor as a maintenance therapy in patients with AML/MDS undergoing allo-SCT (NCT02485535). The primary endpoint was to determine the maximum tolerated dose (MTD) of selinexor after allo-SCT. Patients were enrolled between day 60 to day 100 post allo-SCT if there was no GVHD or disease relapse. Once weekly oral selinexor started approximately 100 days post allo-SCT, and continued for 12 months if tolerated, and there was no relapse of disease. Dose limiting toxicity (DLT) was defined as any grade 3 or higher treatment-related adverse event (AE) that occurred within the first treatment cycle (28 days).

Results: From January 2016 to March 2017, nine patients were enrolled including seven with AML and two with MDS. Selinexor dose levels were 60mg weekly (n=6) and 80mg weekly (n=3). Per stem cell transplant disease risk index (DRI), three patients had high risk and five had intermediate risk. Six patients with AML entered allo-SCT in CR (five CR1, one CR2) and one patient had refractory AML. Two MDS patients had active disease at the time of transplant. Four patients had matched related donors (MRD), two had matched unrelated donors (MUD), and three had haplo/cord SCT. One patient had myeloablative conditioning, and eight had RIC. The median time from allo-SCT to first dose of selinexor was 97 days (range: 66-102). One of the first three patients treated at 60mg weekly developed grade 3 nausea, thus three more patients were enrolled to the 60mg weekly dose level. After no additional DLTs at 60mg weekly, patients were enrolled to 80mg weekly dose level. While there was no DLT during the first cycle treatment at 80mg weekly, the dose of selinexor was decreased to 60mg weekly at the beginning of cycle 2 due to decreased chimerism in one patient and in one in cycle 3 due to neutropenia; one patient stopped treatment in the middle of cycle 2 due to leg cramping. The MTD of selinexor post allo-SCT was determined to be 60mg weekly. The most common AEs were fatigue (67%), anorexia (56%), nausea (56%), vomiting (33%) and diarrhea (22%) which were grades 1-2 with the exception of one case of grade 3 nausea. These AEs were manageable with adequate supportive care, including ondansetron, dexamethasone, megestrol and short hold of drug. One patient is finishing 12 months of treatment without major complications. One patient developed grade 1 skin GVHD during tapering immunosuppression not related to selinexor, and 2 patients developed skin and/or liver GVHD after donor lymphocyte infusion (DLI) for low chimerism, which was not related to selinexor. With median follow-up of 359 (219-639) days from transplant, two patients had disease relapse after 2 and 4 cycles of treatment, of which one patient died from disease progression. Three patients are still on treatment, three patients are off study due to tolerability (Neutropenia=1, fatigue=1; and leg cramping=1), and one patient is off study due to liver GVHD after donor lymphocyte infusion (DLI). The median remission duration from the start of Selinexor treatment was 199 (59-542) days. Correlative studies for MRD monitoring and immune reconstitution are on-going.

Conclusions: Selinexor maintenance after allo-SCT is feasible and tolerable without increased risk of GVHD. The recommended phase II dose of selinexor maintenance post allo-SCT is 60mg weekly. Additional patients are being enrolled to the expansion cohort at the dose of 60mg weekly for better understanding of the toxicities and efficacy.