Selinexor in Combination with Cladribine, Cytarabine and G-CSF for Relapsed or Refractory AML

Selinexor is an oral, reversible, potent Selective Inhibitor of Nuclear Export / SINE^TM compound that specifically blocks the protein Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1). Selinexor induces cell cycle arrest, inhibits DNA damage repair and modulates the expression of NF-κB in cancer cells lines and has demonstrated broad activity across several hematologic malignancies including AML. Our group has previously demonstrated that selinexor restores sensitivity to both cytarabine and anthracycline resistant AML cell lines. Furthermore, combination therapy with selinexor and cytarabine showed additive effects on inhibition of cell proliferation in vitro and prolonged the survival of leukemic mice in vivo . (Rettig et al., ASH 2013). For these reasons, we tested the safety and efficacy of selinexor in combination with chemotherapy in patients with relapsed or refractory AML.

Eligible patients were between 18-70 years of age with AML and either a) primary refractory disease following ≤ 2 cycles of induction chemotherapy, b) first relapse with no prior unsuccessful salvage chemotherapy, or c) relapsed or refractory to hypomethylating agents. Selinexor 60 mg/d was administered on days 1, 5, 10, and 12 in combination with CLAG, (cladribine 5 mg/m²/d on d4-8, cytarabine 2000 mg/m²/d on d4-8 and G-CSF 300 mcg/d on d3-8). The primary endpoint was rate of complete remission (CR + CRi) for selinexor + CLAG per 2003 IWG criteria.

Thirty patients with a median age of 56 years (range 21-70) have been enrolled in the study of which 19 (63%) were treated in first relapse, 10 (33%) failed induction chemotherapy and 1 (3%) was refractory to hypomethylating agent. The complete remission rate for 28 evaluable patients was 50%, (7 CR, 7 CRi). Median time to neutrophil recovery (ANC >1,000/mm³) following treatment was 28 days (range 21-52). Toxicity data is available for the first 27 patients. The most common nonhematologic treatment emergent adverse events included weight loss (n=17, 63%) nausea (16, 59%), mucositis (16, 59%), elevations in AST (15, 56%), ALT (13, 48%), alk phos (13, 48%), and fatigue (13, 48%), the majority of which were G1-2. Serious adverse events occurred in 14 patients, the most frequently due to sepsis (n=6, 22%). Early death within 30 days of the start of treatment occurred only in 1 subject (4%) due to respiratory failure. Of the initial 25 patients treated, 15 have undergone subsequent allogeneic hematopoietic cell transplantation (60%). We conclude that selinexor + CLAG is highly active in patients with relapsed or refractory AML and has encouraging rates of CR. Furthermore, the combination serves as a bridge which allows a high percentage of patients to undergo allogeneic hematopoietic cell transplantation.