Selinexor Highly Active in Relapsed/Refractory AML

Almost half of patients with relapsed/refractory acute myeloid leukemia (AML) achieved complete response (CR) with the combination of selinexor (KPT-330) and AraC-containing chemotherapy, according to data from a small prospective study presented at the 2017 ASH Annual Meeting.

The results showed that 15 of 33 patients had complete responses (45%), including 7 who had complete response with incomplete blood count recovery (CRi). Median time to hematopoietic recovery was 33 days for both platelets and neutrophils.

“Selinexor plus cladribine is highly active in patients with relapsed or refractory AML and has encouraging rates of complete response for a non-anthracycline containing chemotherapy regimen,” said Geoffrey Uy, MD, assistant professor of medical oncology, Washington University in St. Louis. “The combination serves as a bridge, which allows a high percentage of patients to undergo allogeneic hematopoietic cell transplantation.”

He added that correlative studies are underway to determine the effect of selinexor, an exportin 1 (XPO1) antagonist, on regulators of leukemogenesis. Investigators expect to finish patient accrual in January.

Selinexor is a first-in-class agent, hypothesized to work by effecting nuclear retention of tumor suppressors and oncogene mRNAs. Preclinical studies suggested activity in a broad range of hematologic malignancies. The combination of selinexor and AraC demonstrated dramatic activity in a model of AML.

The accumulation of evidence provided a rationale to evaluate selinexor in combination with AraC-based chemotherapy in patients with relapsed/refractory AML. Investigators enrolled adult patients up to age 70 diagnosed who had primary refractory disease after no more than 2 cycles of induction therapy, first relapse with no prior unsuccessful salvage chemotherapy, or who were relapsed/refractory to hypomethylating agents.

Treatment consisted of selinexor plus cladribine, cytarabine, and G-CSF (CLAG). The trial’s primary objective was complete remission (CR or CRi). Secondary objectives included hematologic recovery, event-free survival, overall survival, relapse-free survival, post-treatment rates of hematopoietic cell transplant. Researchers also sought to study the effects of selinexor on nuclear transport, cell cycle, and apoptosis.

The 33 patients enrolled thus far have a median age of 56. Twenty-four patients are men (73%). AML was de novo in 26 patients (79%), and 19 patients were in first relapse (58%) with a median duration of remission of 8 months (range, 1-18). Dr. Uy said 12 patients (36%) had primary refractory disease.

One patient died prior to evaluation of AML status, and the remaining 17 patients (52%) had treatment-resistant disease.

Common all-grade adverse events (AEs) included oral mucositis (64%); weight loss (64%); nausea (58%); diarrhea, vomiting, and fatigue (45% each); chills (36%); and constipation and skin infection (30% each). The most common grade 3/4 AEs were skin infection and sepsis (27% each), bacteremia (24%), and lung infection (21%).

Twenty patients experienced serious AEs, including 7 cases of sepsis and 4 cases of miscellaneous infection. Two patients died of lung infection/respiratory failure during the active treatment, 1 at 30 days and 1 at 60 days.

Uy GL, Rettig MP, Fletcher T, et al. Selinexor in combination with cladribine, cytarabine and G-CSF for relapsed or refractory AML. Presented at: American Society of Hematology 59th Annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 816.